Novel structural motifs consisting of chiral thiazolines: Synthesis, molecular recognition, and anticancer activity

Article abstract of DOI:10.1002/chem.200601446

The facile synthesis of linear and cyclic chiral oligo(4-α/β- methyl)-thiazolines is described. Linear oligothiazolines have been efficiently synthesized by the iterative formation of thiazoline rings and two-directional block condensation. The constructi

Full text of DOI:10.1002/chem.200601446

FULL PAPER
DOI: 10.1002/chem.200601446
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FULL PAPER
Novel Structural Motifs Consistingof Chiral Thiazolines: Synthesis,
Molecular Recognition, and Anticancer Activity
Fu She Han,[a] Hiroyuki Osajima,[b] Mui Cheung,[b] Hidetoshi Tokuyama,[c] and
Tohru Fukuyama*[b]
Abstract: The facile synthesis of linear
and cyclic chiral oligo(4-a/b-methyl)-
thiazolines is described. Linear oligo-
thiazolines have been efficiently syn-
thesized by the iterative formation of
thiazoline rings and two-directional
block condensation. The construction
of 24- to 36-membered cyclic oligothia-
zolines was achieved through the head-
to-tail cyclo-oligomerization of doubly
deprotected linear fragments. Studies
of the interactions of both the linear
and cyclic oligomers with chiral com-
pounds revealed that cyclic oligomers
displayed a strong binding affinity to-
wards mandelic acid, whereas linear
cell lines HPAC, PC-3, and HCT-116.
Studies of the structure–activity rela-
tionships showed that the IC50 values
are clearly dependent on both the
length and the terminal functionalities
of the linear oligomers. Longer deriva-
tives showed more potent activity (e.g.,
hexi- and octithiazolines exhibit IC50 <
1 mm) against all three cancer cell lines.
In sharp contrast, cyclic oligomers were
inactive to all three cell lines.
oligomers showed
a poor affinity.
Linear oligomers have been proven to
inhibit the cell growth of the cancer
Keywords: anticancer agents · mac-
rocycles · molecular recognition ·
oligomerization · thiazolines
Introduction
lecules is that heterocycles, in general, take part in noncova-
lent intermolecular interactions such as hydrogen bonding,
dipole–dipole, and p–p interactions.[1–3] However, the use of
aromatic rings prevents the direct incorporation of chiral
centers into the structural framework.[4] In addition, primari-
ly owing to the lack of general synthetic methodologies,
only limited types of heteroaromatic rings are amenable to
the construction of macromolecules[4] thereby preventing
the flexible design of structurally diverse molecules.
The design and synthesis of macromolecular architectures
possessing defined structural motifs is a key issue in the
areas of molecular recognition,[1] drug design,[2] and supra-
molecular chemistry.[3] The most commonly employed strat-
egy for the construction of such macromolecules involves
the assembly of heteroaromatic subunits. One of the advan-
tages of incorporating heterocyclic structures into macromo-
In one of our synthetic studies of structurally complex
natural products, we focused our attention on oligothiazo-
line marine natural products such as tantazole B (1),[5] mira-
bazole B (2),[6] and thiangazole (3)[7] (Scheme 1), and estab-
[a] Dr. F. S. Han+
PRESTO, The Japan Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[b] H. Osajima, Dr. M. Cheung, Prof. Dr. T. Fukuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5802-8694
E-mail: fukuyama@mol.f.u-tokyo.ac.jp
[c] Prof. Dr. H. Tokuyama++
Graduate School of Pharmaceutical Sciences, PRESTO
The Japan Science and Technology Agency, University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[+] Current Address: National Institute for Materials Science
Namiki, Tsukuba, Ibaraki, 305-0044 (Japan)
[
++] Current Address: Graduate School of Pharmaceutical Sciences,
Tohoku University, Aramaki, Aoba-ku, Sendai 980-8975 (Japan)
Scheme 1. Structures of oligothiazoline marine natural products 1–3.
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T. Fukuyama et al.
lished a synthetic route leading to tantazole B (1).[8] These
compounds consist of a combination of thiazoline subunits
possessing R or S stereochemistry, providing a highly diverse
set of structures. In addition to their structural characteris-
tics, this class of compound displays significant biological ac-
tivity, including antitumor, antifungal, and insecticidal activi-
ties. In view of these characteristics, we considered that a
chiral thiazoline moiety would potentially be a unique sub-
unit with which to construct macromolecules of a defined
chiral architecture and we thus initiated a study of the syn-
thesis and properties of polythiazolines. Herein, we describe
the development of a facile and iterative protocol for the
synthesis of linear and cyclic chiral polythiazolines and an
evaluation of the binding affinity of both linear and cyclic
thiazolines towards chiral molecules and of their antitumor
activity.
to provide thioester 5 (Scheme 3). After removal of the Boc
group with TFA, the thiazoline ring was formed in refluxing
benzene as the monothiazoline unit 6a. Compound 6a was
Results and Discussion
Synthesis of oligothiazolines by the repetitive and block con-
densation protocol:[9] At the outset of this project, we estab-
lished a general and efficient protocol for thiazoline chain
elongation. Although a number of approaches to the assem-
bly of three to four units into linear arrays of oligothiazo-
lines have been developed during synthetic studies on natu-
ral products,[10] these methods are unsatisfactory for the con-
struction of higher homologues owing to their low efficiency.
Accordingly, we have developed a repetitive protocol for
the synthesis of oligothiazolines based on the strategy that
we developed during our synthetic study of tantazole B
(1).[8]
Scheme 3. Reagents and conditions: a) thiobenzoic acid, K2CO3, THF,
08C to RT, 4 h, 94%; b) TFA, RT, benzene, reflux, 84%; c) HS, Et3N
2
(2.5 equiv), CH2Cl2, 08C, 30 min; d) CH2N2 in Et2O (3.0 equiv), THF,
08C (88%, 2 steps); e) BOP-Cl, Et3N, CH2Cl2, RT , 92%; f) T FA, RT ,
benzene, reflux, 96%; g) LiOH, THF–H2O, RT, 100%; h) BOP-Cl, Et3N,
CH2Cl2, RT, 97%; i) TFA, RT, benzene, reflux, 94%; j) LiOH, THF–
H2O, RT, 100%.
As the key intermediate, we used chiral b-lactone 4
(Scheme 2), which is readily prepared from dimethyl N-Boc-
aminomalonate by alkylation, enzymatic desymmetrization,
and b-lactone formation.[8] One of the advantages of this
method is the accessibility of both enantiomers 4 and 4’, po-
tentially enabling us to synthesize both enantiomers of the
target oligothiazolines or alternatively structurally diverse
compounds with various combinations of R and S subunits.
The construction of a thiazoline chain was started by nu-
cleophilic ring-opening of b-lactone 4 with thiobenzoic acid
then condensed with a-methylcysteine derivative 8, a key
fragment in the repetitive elongation of the thiazoline chain
which was prepared by ring-opening of 4 with H2S, followed
by conversion to the methyl ester. The second thiazoline
ring was formed by TFA treatment of 9 and subsequent re-
fluxing in benzene. By repetition of a four-step sequence,
saponification, condensation with 8, removal of the Boc
group, and cyclization under heating, the chiral thiazoline
chain can be elongated in a step-by-step manner to produce
11a.
Furthermore, we have developed a block condensation
protocol for the facile construction of longer thiazoline
chains. We designed a thiazoline oligomer possessing a thia-
zolidinone and an ester function (e.g., segment A or A’ in
Scheme 4) at each terminus as a useful segment for a two-di-
rectional block condensation. The methyl ester and thiazoli-
dinone moieties are chemically orthogonal to each other.
Thus, free carboxylic acid (segment B) could be obtained by
selective hydrolysis of the ester of A under basic conditions.
On the other hand, thiazolidinone could be selectively con-
verted to the corresponding N-Boc-thiol (segment C) by ac-
tivation of the thiazolidinone with the Boc group, followed
by ring-opening by methanolysis. These two segments, B
and C, were then condensed and the resulting product was
treated with TFA and heated to form a thiazoline, thereby
Scheme 2. Preparation of chiral b-lactones.[8]
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Chiral Thiazolines
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Scheme 4. Strategy for two-directional elongation of the oligomer chain.
producing longer thiazoline chains bearing thiazolidinone
and ester functionalities.
The thiazolidinone terminus was formed by removal of
the Boc group in 7, followed by treatment of the resultant
amino-thiol with triphosgene to provide 12 (Scheme 5). Ap-
plication of the repetitive elongation protocol (see above) to
carboxylic acid 12 provided thiazoline 13, which was con-
verted to either carboxylic acid 14 or N-Boc-amino-thiol 15
by chemoselective reactions. These fragments were then
condensed and the resulting thioester intermediate 16 was
treated with TFA and heated to form a further thiazoline
unit, thereby furnishing trimer fragment 17. Repetition of
this sequence provided the thiazoline heptamer 20 efficient-
ly.
By using a combination of the iterative and block conden-
sation protocols, we could efficiently synthesize linear arrays
of oligothiazolines with diverse structures, including mono-
to octithiazoline derivatives 6b, 10a, 11a, and 21a–23a
having a phenyl group at the terminus, the corresponding
opposite enantiomers of 6b, 10a, 11a, and 22a (6’b, 10’a,
11’a, and 22’a, respectively), and mono- to septithiazolines
13, 17, 20, and 24 having a thiazolidinone terminus.
Scheme 5. Reagents and conditions: a) TFA, RT, 15 min; evaporated to
dryness; triphosgene, 20% aq. KOH, dioxane, 08C to RT, 4 h (71%,
2 steps); b) 8 (1.0 equiv), BOP-Cl (1.5 equiv), Et3N (2.5 equiv), CH2Cl2,
RT, 3 h, 79%; c) TFA, RT, 15 min; evaporated to dryness; benzene,
reflux, 2 h, 96%; d) 10% aq. NaOH (1.2 equiv), dioxane/MeOH (4:1
v/v), RT, 30 min, 78%; e) Boc2O (1.2 equiv), Et3N (2.5 equiv), DMAP
(cat.), CH2Cl2, RT, 40 min, quant.; f) NaOMe (1.0m in MeOH)
(1.2 equiv), THF, 08C, 30 min, 81%; g) BOP-Cl (1.5 equiv), Et3N
(2.5 equiv), CH2Cl2, RT, 3 h, 77%; h) TFA, RT, 15 min; evaporated to
dryness; benzene, reflux, 4 h, 93%; i) 10% aq. NaOH (1.2 equiv), diox-
ane/MeOH (4:1 v/v), RT, 30 min, 84%; j) Boc2O (1.2 equiv), Et3N
(2.5 equiv), DMAP (cat.), CH2Cl2, RT, 40 min, 93%; k) NaOMe (1.0m in
MeOH) (1.2 equiv), THF, 08C, 30 min, 81%; l) BOP-Cl (1.5 equiv), Et3N
(2.5 equiv), CH2Cl2, RT, 4 h; m) TFA, RT, 20 min, evaporated to dryness;
benzene, reflux, 4 h (64%, 2 steps).
Synthesis of cyclic oligothiazolines: Having established a
protocol for the synthesis of linear oligothiazolines, our ef-
forts were then directed towards the construction of cyclic
oligothiazolines. We have considered that upon cyclization
of the linear oligothiazoline chains, a chiral, wheel-shaped
binding cavity would be formed, which would give us an op-
portunity to study the binding of chiral host molecules. As
the most straightforward way to form a cyclic compound
should be the cyclization of a linear precursor, we initially
converted 20 into thiol–carboxylic acid 25 (Scheme 6) and
examined its cyclization. However, extensive efforts to cy-
clize 25 proved fruitless, probably as a result of the limited
conformational flexibility of 25.
We eventually found that short fragments of thiol–carbox-
ylic acid underwent smooth cyclodimerization or -trimeriza-
tion in a head-to-tail fashion, affording macrocyclic thioest-
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T. Fukuyama et al.
tration of the substrate. To this end, the use of BOP-Cl led
to the clean formation of a mixture of cyclic dimer 28 and
trimer 29. Other coupling reagents, DCC/HOBt and FDPP,
might also produce the desired cyclic compounds (as detect-
ed by TLC), however, their use resulted in complex mix-
tures. The effect of concentration on the cyclization reaction
was then examined by using BOP-Cl as the coupling re-
agent. At low (2 mm) and high (20 mm) substrate concentra-
tions, cyclization gave a mixture of 28 and 29 in 20 and 36%
total yields, respectively. Surprisingly, the yield was dramati-
cally improved to over 60% when the reaction was carried
out with substrate concentrations of 4 and 8 mm (ratio of 28/
29ꢀ1.8:1 with 4 mm and 1:1 with 8 mm). Thus, the optimal
cyclo-oligomerization conditions are BOP-Cl (2.0 equiv),
Et3N (4.0 equiv), CH2Cl2 (4 mm) at room temperature for
18 h. Under these conditions, the desired cyclic dimer 28
and trimer 29 could be obtained in 63% combined yield. Fi-
nally, treatment of the mixture of cyclic thioesters 28 and 29
with TFA at room temperature, followed by refluxing in
benzene after removal of TFA furnished cyclic octithiazoline
30 and dodecithiazoline 31 in high yields. The two macrocy-
clic compounds could be isolated easily by preparative thin-
layer chromatography (PTLC). Cyclic novithiazoline 33 and
dodecithiazoline 31 were synthesized in a similar manner in
43 and 3% yields over two steps from 32 derived from 24
(Scheme 8).
Scheme 6. Reagents and conditions: a) Boc2O (1.2 equiv), Et3N
(2.5 equiv), DMAP (cat.), CH2Cl2, RT, 1 h; b) 10% aq. NaOH
(2.2 equiv), THF/MeOH (4/1 v/v), 08C to RT, 30 min (81%, 2 steps);
c) BOP-Cl (2.0 equiv), Et3N (4.0 equiv), CH2Cl2 (2 or 4 mm), RT, 36 h.
ers. Thus, compound 17 was converted to thiol–carboxylic
acid 27 (Scheme 7) and its condensation reaction was exam-
ined by using several dehydrating agents, including BOP-Cl/
Et3N, DCC/HOBt, and FDPP, and by changing the concen-
Scheme 8. Synthesis of macrocycles 33 and 31.
The structures of all the linear and cyclic oligothiazolines
were determined by standard spectroscopic techniques, in-
1
cluding H and 13C NMR, high-resolution mass spectrome-
try, and elemental analyses. The structure of cyclic octamer
30 was also confirmed by X-ray crystallographic analysis
(Figure 1).[11] Note that in contrast to the complex NMR
spectra of the linear oligomers, the cyclic oligomers exhibit-
1
ed a simple, single set of signals in their H (Figure 2) and
Scheme 7. Synthesis of macrocycles 30 and 31.
13C NMR spectra.[12] Furthermore, a variable-temperature
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Chiral Thiazolines
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Scheme 9. Structure of micacocidin A.
bonds, could differentiate chiral molecules by forming selec-
tive interactions. As a guest molecule we selected mandelic
acid (MA), a representative chiral a-hydroxy carboxylic
acid,[14] which could form hydrogen bonds at two sites,
through the hydroxy and the carboxy groups.[15]
Figure 1. X-ray crystal structure of macrocycle 30. Displacement ellip-
soids represent 30% probability.
As the simplest case, the interaction between bithiazoline
10a and MA was investigated. Bithiazoline 10a and (R)-MA
were mixed in CDCl3, changing the molar ratio of (R)-MA/
1
10a from 1:1 to 15:1, and their H NMR spectra were deter-
1
mined. Despite careful inspection of the H NMR spectra,
we observed only a slight change in the chemical shifts
(Dd<0.010 ppm), even in the presence of a large excess of
(R)-MA. In the same experiments with (S)-mandelic acid,
no significant change in the chemical shifts was observed. A
longer, linear thiazoline, 22a, consisting of six thiazoline
units, again produced no significant change in the chemical
shifts.
In contrast to the behavior of these linear oligothiazolines,
significant changes in the chemical shifts were observed
when cyclic oligothiazolines were mixed with MA. When
(S)-MA was added to a CDCl3 solution of cyclic octithiazo-
line 30 (1.5”10À3 m), the doublet signals corresponding to
the inward methylene proton Hb at 3.70 ppm (see above)
were shifted upfield (line 2# in Figure 3). The magnitude of
the upfield shift was dependent on the molar ratio of (S)-
MA and reached a plateau with more than 8 equivalents of
(S)-MA. This observation clearly indicates that mandelic
acid has specific interactions with cyclic octithiazoline 30.
The stoichiometry of the interaction was further studied
Figure 2. 1H NMR spectrum of cyclic octithiazoline 30 (the peak at
1.56 ppm corresponds to H2O in the sample.
1H NMR study showed that the spectroscopic properties of
the cyclic oligomers do not change even at À608C. These
observations suggest that the macrocyclic structures are
highly flexible and adopt Cn symmetric conformations in the
solution state (n corresponds to the number of thiazoline
units). A 1D-NOESY study of 30 revealed a strong nuclear
Overhauser effect between the methyl and methylene sig-
nals at d=3.19 ppm (Ha), but no effect was observed be-
tween the methyl and methylene signals at d=3.70 ppm
(Hb), indicating that Ha points outwards from the cyclic
cavity and Hb points inwards.
Bindingstudies : Having synthesized a unique structural
array of chiral oligothiazolines, both in linear and cyclic
forms, we then carried out an investigation into the interac-
tions of these chiral macromolecules with small chiral com-
pounds. As is shown in the metal-chelating structure of mi-
cacocidin A (Scheme 9),[13] the sp2 nitrogen atoms of the
thiazolines act as Lewis bases to bind a metal cation or to
accept hydrogen bonds. In addition, C=N double bonds can
interact with aromatic rings through p–p stacking. Thus, we
believed that the chiral environment of oligothiazolines,
consisting of Lewis basic nitrogen sites and C=N double
Figure 3. 1H NMR titration curves for receptor 30 with mandelic acid
(MA): Line 1# (DdHb of 30·(R)-MA); line 2# (DdHb of 30·(S)-MA);
line 3# (DdHa of 30·(R)-MA); line 4# (DdHa of 30·(S)-MA). All of the ti-
trations were duplicated.
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T. Fukuyama et al.
using the continuous variation method.[16] 1H NMR titration
at a constant total concentration of 5.0”10À3 m indicated
that several possible complexes, such as 1:1, 1:2, 1:4, and 1:8,
were formed between octithiazoline 30 and mandelic acid,
although the 1:4 complex should be the major one, as
judged from the continuous variation titration combined
with Job plots. As a result of the complex interactions, cal-
culation of the association constants was difficult. Interest-
ingly, when (R)-MA was used instead of (S)-MA, much
larger upfield shifts in both the Ha (line 3#) and the Hb sig-
nals (line 1#) were observed (e.g., 1# versus 2#, 3# versus
4#). In addition, in the experiments using either (R)- or (S)-
MA, the upfield shift of the inward proton Hb is always
larger than that of the outward
The inhibitory activities of the linear and cyclic oligothia-
zolines towards cell growth in three cancer cell lines, PC-3,
HCT-116, and HPAC, were evaluated in vitro by using the
WST-1 assay protocol. Although none of the cyclic oligom-
ers (30, 31, and 33), mono-, or bithiazolinecarboxamides
possessed appreciable inhibitory activity, even at high con-
centrations (100 mm), relatively long linear compounds dis-
played distinct activity. In addition, a clear structure–activity
profile was revealed by evaluation of a series of linear oligo-
thiazolines.
As shown in Table 1, the IC values of the linear oligom-
50
ers are affected significantly by the length of the oligomer
chain. Longer chains are generally much more cytotoxic
proton Ha (1# versus 3#, 2#
Table 1. Inhibitory activity against cell growth of tumor cell lines PC-3, HTC-116, and HPAC as a measure of
IC50.[a]
versus 4#). A large upfield shift
of the inward proton can be at-
tributed to the higher shielding
effect due to the phenyl ring of
MA on the inner Hb than on
the outer Ha, suggesting that
MA is buried inside the wheel-
shaped cavity of the macrocycle.
This is possibly the reason why
significant changes in the chemi-
cal shifts were observed in the
NMR spectra of the cyclic oli-
gothiazolines, but not in the
NMR experiments using linear
compounds.
Thiazoline oligomer
IC50 [mm]
PC-3
8.4
HTC-116 HPAC
10c
21c
17.8
5.2[b]
7.9
5.7
7.2
[c]
22a: X=OMe
22b: X=OH
22c: X=NHMe
37.0
8.6
0.7
–
>50
7.3
0.6
7.4
0.7
22c’
n.d.[d]
n.d.[d]
0.4
23a: X=OMe
23b: X=OH
23c: X=NHMe
1.2
24.0
0.3
0.9
19.4
0.5
1.7
31.0
0.6
Similar titration studies of the
other chiral cyclic oligomers,
dodecamer 31 and nonamer 33,
were carried out to show that
these compounds exhibited sim-
[a] Unless otherwise noted, IC50 is the concentration required to inhibit cancer-cell proliferation by 50% after
exposure of the cells to a tested compound for 72 h. [b] Concentration required to inhibit cancer cell prolifera-
tion by 60%. [c] Not available. [d] Not determined.
ilar behavior. Accordingly, NMR titration studies of oligo-
thiazolines clearly indicate that macrocyclic thiazolines rec-
ognize (R)- and (S)-MA by forming specific interactions.
Thus, this class of macrocycle could potentially serve as re-
ceptors for small chiral molecules. Further binding studies
with other types of molecules, such as amino acids, peptides,
oligonucleotides, and sugars, as well as detailed extensive
binding studies to determine binding affinity are currently
under investigation.
than shorter chains. The cytotoxicity of the carboxamide
series of oligomers increases in the order trimer (10c)
tetramer (21c), hexamer (22c), and octamer (23c) as shown
in Table 1, and oligomers with carboxamide functionalities
are generally much more cytotoxic than those with ester and
carboxylic acid functionalities (22c>22b>22a, 23c>23a>
23b, and the ester and carboxylic acid congeners of trimer
10c and tetramer 21c were inactive). This observation is in
agreement with a previous SAR study in which replacement
of the carboxamide moiety in naturally occurring thianga-
zole by other functions, such as thioamide, ester, carboxylic
acid, and aldehyde, generally led to a decrease in biological
activity.[17] The effect of R versus S stereochemistry on bio-
logical activity was also investigated. A comparison of the
cytotoxicity of 22c (0.6 mm) and its enantiomer 22’c (0.4 mm)
against the HPAC cell line revealed that stereochemistry
has little effect on activity.
Biological activity: A number of natural products[5–7] consist-
ing of three to four contiguous thiazolines have demonstrat-
ed significant biological activity, including antitumor, anti-
fungal, and insecticidal properties (Scheme 1). However,
systematic structure–activity relationships (SARs) of this
class of compound and its higher homologues have not yet
been widely studied owing to the lack of an efficient syn-
thetic methodology. As we have developed an efficient pro-
tocol that enables us to access diverse structural analogues
of oligothiazolines, including cyclic and linear forms, pre-
liminary SAR studies on the anticancer activity of various
oligothiazolines were carried out.
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Chiral Thiazolines
FULL PAPER
aqueous layer was extracted with EtOAc (30 mL) three times. The com-
bined organic extracts were dried with MgSO4, filtered, concentrated,
and purified by flash column chromatography on acidic silica gel
(hexane/EtOAc, 6:1) to give thioester 5 (2.86 g, 94%). Thioester 5 was
then treated with TFA at room temperature for 20 min and evaporated
to dryness. The residue was refluxed in benzene (20 mL) for 4 h and then
the solvent was removed to give the crude product. The crude product
was purified by flash column chromatography on silica gel (hexane/
EtOAc, 2:1) to give 6a (1.64 g, 84%). [a]2D5 =À6.5 (c=0.5 in acetone). IR
Conclusion
We have developed an efficient protocol for the synthesis of
both linear and cyclic arrays of chiral oligothiazolines. The
linear oligomers were synthesized by a two-directional block
condensation protocol, followed by acid-mediated thiazoline
ring formation.[8] Construction of 24- to 36-membered cyclic
oligothiazolines was achieved by the head-to-tail cyclo-oligo-
merization of doubly deprotected linear fragments. These
synthetic methods are very quick, versatile, result in high
yields, and have been successfully applied to the synthesis of
new classes of thiazoline/thiazole-based linear and cyclic
oligomers. In addition, both the linear and cyclic oligothia-
zolines are novel structural motifs that exhibit interesting
properties. The linear oligomers display interesting cytotox-
icity against three cancer cell lines, HPAC, PC-3, and HCT-
116. A thorough study of the structure—activity relation-
ships indicated that the IC50 values clearly depend on both
the length and the terminal functionalities of the linear
oligomers. Thus, hexithiazolinecaboxamide 22c and 22’c,
and octithiazoline methyl ester 23a and carboxamide 23c
exhibit strong cytotoxicity with IC50 <1 mm, indicating that
this class of compound could serve as leads in anticancer re-
search. Preliminary studies on chiral recognition revealed
that the cyclic macromolecules possess binding affinity for
mandelic acids, indicating that cyclic oligomers could poten-
tially serve as chiral receptors through hydrogen bonding.
Consequently, the results described in this paper lay the
groundwork for further development of new chiral receptors
and drugs. Extensive studies on the synthesis of new chiral
oligothiazolines employing our methodologies, as well as
their application to the development of artificial receptors
and biologically active compounds such as enzyme inhibitors
and anticancer agents, are currently under investigation.
(neat): n˜ =3173, 2984, 2931, 1732, 1596, 1570, 1456, 1195, 1134, 960 cmÀ1
.
1H NMR ([D6]acetone): d=7.87 (d, J=8.0 Hz, 2H; phenyl), 7.56–7.46
(m, 3H; phenyl), 3.95 (d, J=10.8 Hz, 1H; CH2), 3.44 (d, J=10.8 Hz, 1H;
CH2), 1.61 ppm (s, 3H; CH3); 13C NMR ([D6]acetone): d=174.0, 169.4,
133.1, 133.0, 129.6, 129.3, 84.5, 41.8, 23.8 ppm; MS: [M+ +H]: 222;
HRMS: [M+ +H] calcd for C11H12NO2S: 222.0589; found: 222.0579.
N-Boc-methylcysteine (7): H2S was bubbled through a CH2Cl2 solution
(40 mL) of 4 (4.20 g, 20.9 mmol) and Et3N (7.30 mL, 52.2 mmol) at 08C
for 40 min. The solution was then purged with argon for 10 min and
acidified with 1n HCl to pH 3. The biphasic solution was separated and
the aqueous layer extracted with CH2Cl2 (30 mL) three times. The com-
bined organic extracts were dried with MgSO4, filtered, concentrated,
and purified by flash column chromatography on acidic silica gel
(hexane/EtOAc, 6:1) to give 7 (4.59 g, 94%). [a]2D5 =28.0 (c=3.70 in
CHCl3). IR (neat): n˜ =3400, 2990, 2940, 1700, 1600, 1500, 1450, 1400,
1370, 1300, 1260, 1170, 1060, 780 cmÀ1 1H NMR (CDCl3): d=8.57 (br,
;
1H), 5.67 (br, 1H), 3.10 (m, 2H; CH2), 1.51 (s, 3H; CH3), 1.43 ppm (s,
9H; tert-butyl); 13C NMR (CDCl3): d=178.5, 154.9, 80.0, 60.8, 31.1, 28.4,
23.0; HRMS: [M+ÀC4H8]: calcd for C5H9NO4S: 179.0252; found:
179.0251.
N-Boc-methylcysteine methyl ester (8):
A diethyl ether solution of
CH2N2 (10.4 mmol) was added dropwise to a solution of 7 (810 mg,
3.46 mmol) in THF (15 mL) at 08C. The resulting solution was stirred for
an additional 30 min. The reaction was terminated by the addition of
acetic acid dropwise until the solution became colorless. The solvent was
evaporated and the residue purified by flash column chromatography on
silica gel (hexane/EtOAc 20:1) to give 8 (815 mg, 94%). [a]2D5 =8.1 (c=
1
0.50 in CHCl3). H NMR (CDCl3): d=5.48 (br, 1H), 3.78 (s, 3H; OCH3),
3.05 (d, J=9.2 Hz, 1H; CH2), 3.01 (d, J=9.2 Hz, 1H; CH2), 1.56 (s, 3H;
CH3), 1.45 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3): d=173.5, 154.0,
79.8, 60.8, 52.8, 30.7, 28.2, 22.9 ppm; MS: [M++H]: 250; HRMS: [M+
+H]: calcd for C10H20NO4S: 250.1113; found: 250.1119.
General procedure for the synthesis of linear oligothiazoline methyl
esters: procedure A: BOP-Cl (1.5 equiv) and Et3N (2.0 equiv) were
added to a CH2Cl2 solution of thiol (1.0 equiv) and carboxylic acid
(1.0 equiv) and the resulting mixture was stirred at room temperature for
2–4 h. The solution was then washed with 5% aq. NaHCO3 and brine
after being diluted with EtOAc. The organic layer was dried with
MgSO4, concentrated, and purified by flash column chromatography on
silica gel (hexane/EtOAc 4:1) to give the thioester. The pure thioester in-
termediate was then treated with neat TFA at room temperature for
20 min and evaporated to dryness. The residue was dissolved in benzene
and refluxed for 4 h and then evaporated to leave crude products. The
crude products were purified by flash column chromatography on silica
gel (hexane/EtOAc, 2:1) to give the corresponding linear oligothiazoline.
Experimental Section
General methods: Unless otherwise noted, all reagents were reagent
grade and were used without purification. All solvents were purified ac-
cording to standard procedures. IR spectra were recorded with a JASCO
FT/IR-410 spectrometer and only selected absorbencies are reported. 1H
and 13C NMR spectra were recorded at 400 and 100 MHz, respectively,
with a JEOL JNM-LA400 instrument. Chemical shifts are given relative
to TMS or the appropriate solvent peak. Mass spectra (MS) and high-res-
olution mass spectra (HRMS) were measured using a JEOL JMS-700 or
a JEOL JMS-GCmate instrument. Elemental analyses were carried out
on a Yanagimoto MT-6 CHN CORDER instrument. Optical rotations
were measured using a JASCO DIP-100 Digital Polarimeter. Analytical
thin-layer chromatography (TLC) separations were performed on Merck
analytical plates precoated with silica gel 60 F254 (0.25 mm thick). Prepa-
rative TLC separations were performed on Merck analytical plates (0.25
or 0.50 mm thick) precoated with silica gel 60 F254. Flash chromatogra-
phy separations were performed on Kanto Chemical Silica Gel 60
(normal or neutral, 40–100 mesh).
Thiazoline thioester 9: Thioester 9 was obtained in 92% yield from 6a
and 8 according to the general procedure A. [a]2D5 =À102.0 (c=0.70 in
CHCl3). IR (neat): n˜ =3385, 2977, 2934, 2870, 1744, 1714, 1685, 1492,
1449, 1366, 1258, 1167, 1057, 957, 767 cmÀ1 1H NMR (CDCl3): d=7.91
;
(d, J=9.2 Hz, 2H; phenyl), 7.52–7.43 (m, 3H; phenyl), 3.79–3.75 (m, 4H;
OCH3 and CH2), 3.65 (d, J=11.2 Hz, 1H; CH2), 3.56 (d, J=12.0 Hz, 1H;
CH2), 3.33 (d, J=11.2 Hz, 1H; CH2), 1.67 (s, 3H; CH3), 1.42 (s, 9H; tert-
butyl), 1.41 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=203.6, 173.3, 170.3,
154.1, 132.7, 131.8, 128.5 (2C), 90.3, 79.9, 59.1, 52.8, 42.0, 34.6, 28.2, 25.1,
25.0 ppm; MS [M++H]: 453; HRMS [M++H]: calcd for C21H29N2O5S2:
453.1518; found: 453.1529.
Monothiazolinecarboxylic acid 6a: Thiobenzoic acid (1.30 mL,
11.0 mmol) and K2CO3 (3.71 g, 26.8 mmol) were added to a solution of 4
(1.80 g, 8.96 mmol) in THF (40 mL) at 08C. The resulting solution was
stirred at room temperature for 4 h. The reaction mixture was acidified
with 10% aq. KHSO4 to pH 4 after being diluted with EtOAc. Separated
Bithiazoline methyl ester 10a: Methyl ester 10a was obtained in 96%
yield from 9 according to the general procedure A. [a]2D5 =À156.4 (c=
0.51 in CHCl3). IR (neat): n˜ =2979, 2930, 2853, 1738, 1615, 1447, 1291,
Chem. Eur. J. 2007, 13, 3026 – 3038
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3033

T. Fukuyama et al.
1
1230, 1122, 1016, 958 cmÀ1. H NMR (CDCl3): d=7.88 (d, J=7.6 Hz, 2H;
CH2), 1.55 ppm (s, 3H; CH3); 13C NMR (CD3OD): d=178.1, 176.3, 65.3,
40.2, 24.5 ppm; MS: [M++H]: 162; HRMS: [M++H]: calcd for
C5H8NO3S: 162.0225; found: 162.0227.
phenyl), 7.49–7.42 (m, 3H; phenyl), 3.93 (d, J=11.2 Hz, 1H; CH2), 3.81
(s, 3H; OCH3), 3.72 (d, J=10.8 Hz, 1H; CH2), 3.48 (d, J=10.8 Hz, 1H;
CH2), 3.12 (d, J=12.0 Hz, 1H; CH2), 1.72 (s, 3H; CH3), 1.54 ppm (s, 3H;
CH3); 13C NMR (CDCl3): d=178.4, 173.8, 168.5, 132.8, 131.6, 128.5 (2C),
83.9 (2C), 52.8, 43.2, 41.1, 26.0, 23.9 ppm; MS: [M++H]: 335; HRMS:
[M++H]: calcd for C16H19N2O2S2: 335.0888; found: 335.0892.
2-Oxothiazolidinylthiazoline 13: Compound 13 was obtained in 75%
yield from 12 according to the general procedure A. [a]2D5 =À108.8 (c=
0.65 in CHCl3). IR (neat): n˜ =3287, 2984, 2936, 1735, 1698, 1684, 1457,
1437, 1294, 1238, 1203, 1128, 1020 cmÀ1 1H NMR (CDCl3): d=6.15 (s,
;
1H; NH), 3.78–3.83 (m, 5H; OCH3 and CH2), 3.38 (d, J=10.8 Hz, 1H;
CH2), 3.24 (d, J=10.8 Hz, 1H; CH2), 1.68 (s, 3H; CH3), 1.55 ppm (s, 3H;
CH3); 13C NMR (CDCl3): d=176.3, 173.8, 173.1, 84.7, 62.9, 53.0, 42.3,
40.5, 25.8, 23.6 ppm; MS: [M++H]: 275; HRMS: [M++H]: calcd for
C10H15N2O3S2: 275.0524; found: 275.0516.
General procedure for the preparation of oligothiazoline carboxylic
acids: procedure B: A 10% aq. LiOH solution (3.0 equiv) was added to
a THF solution of oligothiazoline methyl ester (1.0 equiv) at 08C. The re-
sulting solution was then stirred at room temperature for 30 min. The re-
action mixture was acidified with 10% KHSO4 to pH 5–6 after being di-
luted with EtOAc. After extracting the aqueous layer with EtOAc three
times, the combined organic layers were dried with MgSO4, filtered, con-
centrated, and purified by flash column chromatography on acidic silica
gel (hexane/EtOAc, 1:1) to give the corresponding oligothiazoline car-
boxylic acid.
2-Oxothiazolidinylthiazolinecarboxylic acid 14: Compound 14 was ob-
tained in 78% yield from 13 according to the general procedure B.
[a]2D5 =À38.6 (c=0.50 in acetone). IR (neat): n˜ =3345, 2990, 2936, 2860,
1
1732, 1710, 1684, 1457, 1437, 1296, 1238, 1203, 1128, 1021 cmÀ1; H NMR
([D6]acetone): d=7.73 (br, 1H), 3.80 (t, J=12.0 Hz, 2H; CH2), 3.49 (d,
J=10.8 Hz, 1H; CH2), 3.32 (d, J=10.8 Hz, 1H; CH2), 1.66 (s, 3H; CH3),
1.53 ppm (s, 3H; CH3); 13C NMR ([D6]acetone): d=177.2, 173.7, 172.6,
85.2, 63.3, 42.2, 40.8, 25.5, 23.4 ppm; MS: [M++H]: 261; HRMS: [M+
+H]: calcd for C9H13N2O3S2: 261.0368; found: 261.0369.
Bithiazolinecarboxylic acid 10b: Carboxylic acid 10b was obtained in
quantitative yield from 10a according to the general procedure B. [a]D25
=
À201.6 (c=0.68 in CHCl3). IR (neat): n˜ =3340, 2982, 2929, 2865, 1731,
1608, 1577, 1447, 1250, 1176, 1017, 958 cmÀ1 1H NMR (CDCl3): d=7.87
;
(d, J=7.2 Hz, 2H; phenyl), 7.51–7.43 (m, 3H; phenyl), 3.88 (d, J=
12.0 Hz, 1H; CH2), 3.70 (d, J=12.0 Hz, 1H; CH2), 3.45 (d, J=11.2 Hz,
1H; CH2), 3.23 (d, J=11.2 Hz, 1H; CH2), 1.73 (s, 3H; CH3), 1.56 ppm (s,
3H; CH3); 13C NMR (CDCl3): d=181.1, 176.1, 169.2, 132.6, 131.8, 128.6,
83.7, 83.6, 43.1, 40.8, 25.9, 24.0 ppm; MS: [M++H]: 321; HRMS: [M+
+H]: calcd for C15H17N2O2S2: 321.0731; found: 321.0730.
N-Boc-amino-thiol–monothiazoline 15: Boc2O (713 mg, 3.27 mmol), Et3N
(759 mL, 5.45 mmol), and DMAP (30 mg, 5% w/w) were added to a
CH2Cl2 (10 mL) solution of 13 (600 mg, 2.18 mmol) at 08C. The resulting
solution was stirred at room temperature for 1 h and washed with 5%
aq. KHSO4, saturated NaHCO3, and brine after being diluted with
EtOAc. The organic layer was then dried with MgSO4, filtered, concen-
trated, and purified by flash column chromatography on silica gel
(hexane/EtOAc, 4:1) to give the desired N-Boc thiazolidinone (814 mg,
quantitative yield). [a]2D5 =À77.0 (c=1.00 in CHCl3). IR (neat): n˜ =2982,
Terthiazoline methyl ester 11a: Methyl ester 11a was obtained in 91%
yield from 10b according to the general procedure A. [a]2D5 =À339.0 (c=
0.22 in CHCl3). IR (neat): n˜ =2976, 2945, 2861, 1737, 1618, 1576, 1447,
2934, 1774, 1734, 1372, 1284, 1257, 1155, 1125, 941 cmÀ1 1H NMR
;
1367, 1284, 1233, 1122, 1013, 958, 767 cmÀ1 1H NMR (CDCl3): d=7.87
;
(CDCl3): d=3.81 (d, J=11.6 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.53 (d,
J=11.6 Hz, 1H; CH2), 3.26 (d, J=11.2 Hz, 1H; CH2), 3.07 (d, J=10.8,
CH2), 1.94 (s, 3H; CH3), 1.51 (s, 3H; CH3), 1.50 ppm (s, 9H; tert-butyl);
13C NMR (CDCl3): d=173.9, 172.7, 169.2, 148.2, 84.2, 84.1, 67.2, 52.6,
41.9, 37.0, 27.6, 23.0, 22.8 ppm; MS: [M++H]: 375; HRMS: [M++H]:
calcd for C15H23N2O5S2: 375.1048; found: 375.1032.
(d, J=7.2 Hz, 2H; phenyl), 7.49–7.40 (m, 3H; phenyl), 3.92 (d, J=
10.8 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.72 (d, J=12.0 Hz, 1H; CH2),
3.71 (d, J=11.6 Hz, 1H; CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.28 (d,
J=12.0 Hz, 1H; CH2), 3.11 (d, J=11.2 Hz, 1H; CH2), 1.74 (s, 3H; CH3),
1.61 (s, 3H; CH3), 1.55 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=178.4,
178.3, 173.7, 168.6, 132.8, 131.6, 128.6, 128.5, 84.0, 83.9, 83.5, 52.8, 43.3,
43.0, 41.1, 26.1, 25.8, 23.9 ppm; MS: [M+]: 433; HRMS: [M++H]: calcd
for C20H24N3O2S3: 434.1031; found: 434.1058; elemental analysis calcd
(%) for C20H23N3O2S3·0.5H2O: C 54.27, H 5.46, N 9.49; found: C 54.59,
H 5.31, N 9.23.
NaOMe (0.54 mmol, 1.0m in MeOH) was added to a THF (3 mL) solu-
tion of N-Boc-thiazolidinone (168 mg, 0.45 mmol) at 08C and the result-
ing mixture was stirred for an additional 30 min. The solution was acidi-
fied with 10% KHSO4 to pH 5–6 after being diluted with EtOAc at 08C.
The aqueous layer was extracted with EtOAc (15 mL) three times. The
combined organic extracts were dried with MgSO4, filtered, concentrated,
and purified by flash column chromatography on silica gel (hexane/
EtOAc, 6:1) to give 15 (126 mg, 81%). [a]2D5 =À15.4 (c=0.50 in CHCl3).
IR (neat): n˜ =3392, 2979, 2932, 1739, 1718, 1616, 1490, 1456, 1368, 1282,
Terthiazolinecarboxylic acid 11b: Carboxylic acid 11b was obtained in
97% yield from 11a according to the general procedure B. [a]2D5 =À342
(c=0.42 in CHCl3). IR (neat): n˜ =3358, 2977, 2929, 2860, 1731, 1717,
1616, 1575, 1447, 1371, 1254, 1176, 1015, 958, 767 cmÀ1 1H NMR
;
(CDCl3): d=7.87 (d, J=7.2 Hz, 2H; phenyl), 7.50–7.43 (m, 3H; phenyl),
3.90 (d, J=11.2 Hz, 1H; CH2), 3.69 (d, J=12.0 Hz, 1H; CH2), 3.68 (d,
J=11.2 Hz, 1H; CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.25 (d, J=
11.2 Hz, 1H; CH2), 3.24 (d, J=12.0 Hz, 1H; CH2), 1.73 (s, 3H; CH3),
1.62 (s, 3H; CH3), 1.57 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=180.4,
179.3, 175.7, 168.9, 132.8, 131.7, 128.5 (2C), 83.9, 83.8, 83.4, 43.2, 42.9,
40.7, 25.9, 25.8, 24.0 ppm; MS: [M++H]: 420; HRMS: [M++2H]: calcd
for C19H23N3O2S3: 421.0952; found: 421.0970; elemental analysis calcd
(%) for C19H21N3O2S3·0.5H2O: C 53.24, H 5.17, N 9.80; found: C 53.48, H
5.35, N 9.34.
1245, 1166, 1123, 1063, 1011 cmÀ1 1H NMR (CDCl3): d=5.67 (br, 1H;
;
NH), 3.77 (m, 5H; OCH3 and CH2), 3.18 (m, 2H; CH2), 1.61 (s, 3H;
CH3), 1.51 (s, 3H; CH3), 1.44 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3):
d=173.0, 153.8, 83.7, 59.0, 52.6, 41.7, 32.4, 24.7, 28.1, 23.3 ppm; MS: [M+
+H]: 349; HRMS: [M+]: calcd for C14H24N2O4S2: 348.1177; found:
348.1194.
Thioester 16: Thioester 16 was obtained in 77% yield from 14 and 15 ac-
cording to the general procedure A. [a]2D5 =À20 (c=0.50 in CHCl3). IR
(neat): n˜ =3379, 3303, 2978, 2930, 1730, 1715, 1698, 1684, 1616, 1507,
1
1489, 1456, 1368, 1286, 1248, 1164, 1012 cmÀ1; H NMR (CDCl3): d=6.64
2-Oxothiazolidinecarboxylic acid 12: N-Boc-methylcysteine
7 (3.30 g,
(br, 1H; NH), 5.88 (br, 1H; NH), 3.85–3.62 (m, 8H; OCH3 and CH2),
3.43 (d, J=11.2 Hz, 1H; CH2), 3.20 (d, J=11.2 Hz, 1H; CH2), 3.19 (d,
J=12.0 Hz, 1H; CH2), 1.81 (s, 3H; CH3), 1.61 (s, 3H; CH3), 1.59 (s, 3H;
CH3), 1.50 (s, 3H; CH3), 1.44 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3):
d=202.8, 179.9, 175.7, 173.6, 153.7, 90.7, 83.6, 79.6, 63.0, 58.7, 53.2, 52.8,
42.8, 42.0, 40.8, 35.9, 29.6, 28.3, 25.2, 24.8, 22.9 ppm; MS: [M++H]: 591;
HRMS: [M++H]: calcd for C23H35N4O6S4: 591.1439; found: 591.1423.
14.1 mmol) was treated with neat TFA (10 mL) at room temperature for
20 min and evaporated to dryness. The residue was dissolved in 20% aq.
KOH (40 mL) and cooled to 08C. A dioxane solution (40 mL) of triphos-
gene (1.40 g, 19.7 mmol) was added slowly over 20 min. After stirring for
an additional 1 h, the ice-bath was removed and the solution was stirred
at room temperature for 3 h. The solution was acidified with 1n HCl to
pH 3 and extracted thoroughly with EtOAc (50 mL) five times. The com-
bined organic extracts were dried with MgSO4, filtered, and concentrated
to give a crude product, which was then crystallized from acetone/ether
to give pure 12 (1.59 g, 71% yield). [a]2D5 =À92.4 (c=0.5 in MeOH). IR
2-Oxothiazolidinylterthiazoline methyl ester 17: Methyl ester 17 was ob-
tained in 93% yield from 16 according to the general procedure A.
[a]2D5 =À248.4 (c=0.95 in CHCl3). IR (neat): n˜ =3294, 2977, 2929, 2857,
(neat): n˜ =3417, 3225, 2982, 2940, 2870, 1680, 1618 cmÀ1
;
1H NMR
1735, 1701, 1684, 1624, 1437, 1372, 1013 cmÀ1; H NMR (CDCl3): d=5.76
1
(CD3OD): d=3.72 (d, J=10.8 Hz, 1H; CH2), 3.36 (d, J=10.8 Hz, 1H;
(br, 1H; NH), 3.84 (d, J=11.2 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.78
3034
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3026 – 3038

Chiral Thiazolines
FULL PAPER
(d, J=12.0 Hz, 1H; CH2), 3.72 (d, J=11.2 Hz, 1H; CH2), 3.70 (d, J=
10.8 Hz, 1H; CH2), 3.41 (d, J=11.6 Hz, 1H; CH2), 3.38 (d, J=11.6 Hz,
1H; CH2), 3.28 (d, J=12.0 Hz, 1H; CH2), 3.10 (d, J=10.8 Hz, 1H; CH2),
1.70 (s, 3H; CH3), 1.64 (s, 3H; CH3), 1.60 (s, 3H; CH3), 1.54 ppm (s, 3H;
CH3); 13C NMR (CDCl3): d=177.9, 177.3, 176.2, 173.7, 84.3, 84.0, 83.6,
62.9, 52.7, 44.1, 43.0, 41.1, 40.4, 26.0, 25.8, 25.5, 23.9 ppm; MS: [M++H]:
473; HRMS: [M++H]: calcd for C18H25N4O3S4: 473.0809; found:
473.0812.
519.1017; found: 519.1003; elemental analysis calcd (%) for
C23H26N4O2S4·0.5H2O: C 52.43, H 5.22, N 10.97; found: C 52.37, H 5.15,
N, 10.62.
Sexithiazoline methyl ester 22a: Methyl ester 22a was obtained in 85%
yield from 11b and the thiol derived from 24 according to the general
procedure A. [a]2D5 =À399.4 (c=0.5 in CHCl3). IR (neat): n˜ =3406, 2976,
1
2924, 2866, 1673, 1624, 1602, 1528, 1444, 1434, 1363, 1011 cmÀ1; H NMR
(CDCl3): d=7.87 (d, J=7.2 Hz, 2H; phenyl), 7.48–7.42 (m, 3H; phenyl),
3.92 (d, J=11.2 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.72–3.68 (m, 5H;
CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.29–3.24 (m, 4H; CH2), 3.09 (d,
J=11.2 Hz, 1H; CH2), 1.74 (s, 3H; CH3), 1.64 (s, 3H; CH3), 1.63 (s, 3H;
CH3), 1.62 (s, 3H; CH3), 1.60 (s, 3H; CH3), 1.53 ppm (s, 3H; CH3); 13C
NMR (CDCl3): d=178.5, 178.4, 178.3, 178.2 (2C), 173.8, 168.5, 132.8,
131.6, 128.6, 128.5, 84.0, 83.7, 83.6 (2C), 52.8, 43.3, 43.1, 43.0, 42.9, 41.1,
26.0, 25.9, 25.8 (2C), 23.9 ppm; MS: [M++H]: 732; elemental analysis
calcd (%) for C32H38N6O2S6·H2O: C 51.31, H 5.38, N 11.22; found: C
51.21, H 5.21, N 10.88.
2-Oxothiazolidinylterthiazolinecarboxylic acid 18: Compound 18 was ob-
tained in 84% yield from 17 according to the general procedure B.
[a]2D5 =À210.3 (c=0.5, acetone). IR (neat): n˜ =3203, 2972, 2929, 2864,
1699, 1675, 1618, 1016 cmÀ1 1H NMR ([D6]acetone): d=5.86 (s, 1H;
;
NH), 3.84 (d, J=12.0 Hz, 1H; CH2), 3.77 (d, J=12.0 Hz, 1H; CH2), 3.68
(d, J=11.0 Hz, 2H; CH2), 3.39 (t, J=12.0 Hz, 2H; CH2), 3.26 (d, J=
12.0 Hz, 1H; CH2), 3.21 (d, J=12.0 Hz, 1H; CH2), 1.69 (s, 3H; CH3),
1.63 (s, 3H; CH3), 1.61 (s, 3H; CH3), 1.56 ppm (s, 3H; CH3); 13C NMR
([D6]acetone): d=178.2, 177.5, 174.2, 172.7, 85.2, 84.5, 84.4, 44.1, 43.2,
41.6, 41.1, 26.2, 25.69, 25.7, 23.8 ppm; MS: [M++2H]: 460; HRMS: [M+
+2H]: calcd for C17H24N4O3S4: 460.0731; found: 460.0712.
Sexithiazolinecarboxylic acid 22b: Carboxylic acid 22b was obtained in
94% yield from 22a according to the general procedure B. [a]2D5 =À419.6
(c=0.24 in CHCl3). IR (neat): n˜ =3200, 2970, 2926, 2849, 1731, 1624,
N-Boc-amino-thiol–terthiazoline 19: Compound 19 was obtained in 75%
yield from 17 according to the procedure for the preparation of 15.
[a]2D5 =À121.2 (c=0.50 in CHCl3). IR (neat): n˜ =3390, 2978, 2932, 1739,
1
1602, 1452, 1432, 1362, 1253, 1181, 1011, 957 cmÀ1; H NMR (CDCl3): d=
7.87 (d, J=7.2 Hz, 2H; phenyl), 7.49–7.40 (m, 3H; phenyl), 3.92 (d, J=
10.8 Hz, 1H; CH2), 3.73–3.65 (m, 5H; CH2), 3.46 (d, J=11.2 Hz, 1H;
CH2), 3.29–3.21 (m, 5H; CH2), 1.74 (s, 3H; CH3), 1.63 (s, 6H; CH3), 1.62
(s, 3H; CH3), 1.61 (s, 3H; CH3), 1.55 ppm (s, 3H; CH3); 13C NMR
(CDCl3): d=180.4, 179.0, 178.7, 178.6, 178.5, 175.3, 168.7, 132.8, 131.6,
128.6, 128.5, 84.0, 83.8, 83.6 (2C), 83.5, 43.3, 43.1, 43.0, 42.9, 42.8, 40.7,
26.0, 25.9 (2C), 25.8, 24.1 ppm; MS: [M+ÀH]: 715; HRMS: [M+ÀH]:
calcd for C31H35N6O2S6: 715.1146; found: 715.1123; elemental analysis
calcd (%) for C31H36N6O2S6·0.75H2O: C 51.04, H 5.18, N 11.52; found: C
51.23, H 5.21, N 11.88.
1720, 1614, 1490, 1456, 1368, 1281, 1245, 1166, 1125, 1064, 1012 cmÀ1 1H
;
NMR (CDCl3): d=5.66 (br, 1H; NH), 3.79–3.76 (m, 5H; OCH3 and
CH2), 3.72 (d, J=10.8 Hz, 1H; CH2), 3.70 (d, J=12.0 Hz, 1H; CH2), 3.36
(d, J=11.6 Hz, 1H; CH2), 3.28 (d, J=10.8 Hz, 1H; CH2), 3.18–3.10 (m,
2H; CH2), 1.62 (s, 3H; CH3), 1.61 (s, 3H; CH3), 1.59 (s, 3H; CH3),
1.54 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=178.1, 177.5, 173.7, 153.9,
84.0, 83.6, 83.5, 80.1, 59.3, 52.8, 43.3, 43.0, 41.1, 28.3, 26.0, 25.4, 23.9 ppm;
MS: [M++H]: 547; HRMS: [M++H]: calcd for C22H35N4O4S4: 547.1541;
found: 547.1438.
2-Oxothiazolidinylseptithiazoline methyl ester 20: Methyl ester 20 was
obtained in 64% yield from 18 and 19 according to the general procedure
A. [a]2D5 =À322.2 (c=0.50 in CHCl3). IR (neat): n˜ =3294, 2977, 2929,
Octithiazoline methyl ester 23a: Methyl ester 23a was obtained in 83%
yield from 21b and 19 according to the general procedure A. [a]D25
=
À402.4 (c=0.25 in CHCl3). IR (neat): n˜ =3405, 2978, 2924, 2868, 1674,
1
2857, 1735, 1701, 1684, 1624, 1437, 1372, 1013 cmÀ1
;
1H NMR (CDCl3):
1625, 1604, 1528, 1445, 1435, 1363, 1012 cmÀ1; H NMR (CDCl3): d=7.87
d=5.70 (s, 1H; NH), 3.85 (d, J=11.0 Hz, 1H; CH2), 3.78–3.68 (m, 6H;
CH2), 3.43–3.36 (m, 4H; CH2), 3.28–3.22 (m, 4H; CH2), 3.09 (d, J=
11.0 Hz, 1H; CH2), 1.69 (s, 3H; CH3), 1.64 (s, 3H; CH3), 1.63 (s, 3H;
CH3), 1.62 (s, 3H; CH3), 1.59 (s, 3H; CH3),1.56 (s, 6H; CH3), 1.53 ppm
(s, 3H; CH3); 13C NMR (CDCl3): d=178.6, 178.1, 178.0, 177.4, 175.9,
173.7, 173.4, 84.3, 84.0, 83.7 (2C), 83.6, 44.1, 43.1, 42.8, 42.7, 41.1, 40.3,
26.3, 26.2, 25.8, 25.6, 23.9 ppm; MS: [M++H]: 869; HRMS: [M++H]:
calcd for C34H45N8O3S8: 869.1380; found: 869.1377.
(d, J=7.2 Hz, 2H; phenyl), 7.49–7.42 (m, 3H; phenyl), 3.92 (d, J=
11.2 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.72–3.68 (m, 7H; CH2), 3.46 (d,
J=12.0 Hz, 1H; CH2), 3.28–3.24 (m, 6H; CH2), 3.09 (d, J=12.0 Hz, 1H;
CH2), 1.74 (s, 3H; CH3), 1.63 (S, 3H; CH3), 1.62 (s, 3H; CH3), 1.60 (s,
3H; CH3), 1.57 (s, 9H; CH3), 1.53 ppm (s, 3H; CH3); 13C NMR (CDCl3):
d=178.5, 178.4, 178.3, 178.2, 173.8, 168.5, 132.8, 131.6, 128.6, 128.5, 84.0,
83.7, 83.6, 52.8, 43.3, 43.1, 43.0, 42.9, 41.1, 26.0, 25.9, 25.8, 23.9 ppm; MS:
[M++H]: 929; elemental analysis calcd (%) for C40H48N8O2S8: C 51.69, H
5.21, N 12.06; found: C 51.45, H 5.31, N 11.99.
Quaterthiazoline methyl ester 21a: Methyl ester 21a was obtained in
88% yield from 10b and 15 according to the general procedure A.
[a]2D5 =À388.2 (c=0.46 in CHCl3). IR (neat): n˜ =2977, 2945, 2862, 1737,
Octithiazolinecarboxylic acid 23b: Carboxylic acid 23b was obtained in
95% yield from 23a according to the general procedure B. [a]2D5 =À422.1
(c=0.15 in CHCl3). 1H NMR (CDCl3): d=7.88 (d, J=6.4 Hz, 1H;
phenyl), 7.49–7.40 (m, 3H; phenyl), 3.92 (d, J=12.0 Hz, 1H; CH2), 3.74–
3.64 (m, 7H; CH2), 3.46 (d, J=12.0 Hz, 1H; CH2), 3.29–3.20 (m, 7H;
CH2), 1.74 (s, 3H; CH3), 1.66 (s, 3H; CH3), 1.64 (s, 6H; CH3), 1.63 (s,
3H; CH3), 1.62 (s, 3H; CH3), 1.61 (s, 3H; CH3), 1.55 ppm (s, 3H; CH3);
13C NMR (CDCl3): d=180.4, 179.0, 178.7, 178.6, 178.5, 175.3, 168.7,
132.8, 131.6, 128.6, 128.5, 84.0, 83.8, 83.6 (2C), 83.5, 43.3, 43.1, 43.0, 42.9,
42.8, 40.7, 26.0, 25.9 (2C), 25.8, 24.1 ppm; MS: [M++H]: 915; elemental
analysis calcd (%) for C39H46N8O2S8·0.75H2O: C 50.43, H 5.15, N 12.06;
found: C 50.63, H 5.10, N 12.31.
1618, 1577, 1448, 1367, 1284, 1234, 1122, 1013, 958, 767 cmÀ1 1H NMR
.
(CDCl3): d=7.88 (d, J=6.8 Hz, 2H; phenyl), 7.49–7.40 (m, 3H; phenyl),
3.92 (d, J=12.0 Hz, 1H; CH2), 3.80 (s, 3H; OCH3), 3.73–3.69 (m, 3H;
CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.36 (d, J=11.2 Hz, 1H; CH2), 3.26
(d, J=11.2 Hz, 1H; CH2), 3.10 (d, J=12.0 Hz, 1H; CH2), 1.74 (s, 3H;
CH3), 1.63 (s, 3H; CH3), 1.62 (s, 3H; CH3), 1.54 ppm (s, 3H; CH3); 13C
NMR (CDCl3): d=178.5, 178.2 (2C), 173.7, 168.5, 132.8, 131.5, 128.5
(2C), 128.4 (2C), 84.0 (2C), 83.6 (2C), 52.8, 43.2, 43.0, 42.9, 41.0, 226.0,
25.8 (2C), 23.8 ppm; MS: [M+]: 532; HRMS: [M++H]: calcd for
C24H29N4O2S4: 533.1173; found: 533.1192; elemental analysis calcd (%)
for C24H28N4O2S4: C 54.11, H 5.30, N 10.52; found: C 53.89, H 5.34;
10.35.
2-Oxothiazolidinylbithiazoline 24: Compound 24 was obtained in 72%
yield over two steps from 14 and 8 according to the general procedure A.
[a]2D5 =À203.3 (c=0.50 in CHCl3). IR (neat): n˜ =3340, 2983, 2940, 1734,
Quaterthiazolinecarboxylic acid 21b: Carboxylic acid 21b was obtained
in 99% yield from 21a. [a]2D5 =À376.2 (c=0.5 in CHCl3). IR (neat): n˜ =
3360, 2978, 2930, 2863, 1733, 1719, 1616, 1575, 1447, 1371, 1254, 1177,
1698, 1681, 1656, 1618, 1558, 1541, 1507, 1284, 1223, 1125, 1017, 772 cmÀ1
;
1H NMR (CDCl3): d=5.98 (br, 1H; NH), 3.85 (d, J=12.0 Hz, 1H; CH2),
3.81 (s, 3H; OCH3), 3.77 (d, J=11.2 Hz, 1H; CH2), 3.71 (d, J=11.2 Hz,
1H; CH2), 3.43 (d, J=12.0 Hz, 1H; CH2), 3.38 (d, J=11.2 Hz, 1H; CH2),
3.11 (d, J=12.0 Hz, 1H; CH2), 1.69 (s, 3H; CH3), 1.60 (s, 3H; CH3),
1.54 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=177.4, 176.2, 174.2, 173.6,
84.2, 83.9, 63.0, 52.8, 43.9, 41.1, 40.4, 25.7, 25.6, 23.1 ppm; MS: [M++H]:
374; HRMS: [M++H]: calcd for C14H20N3O3S3: 374.0667; found:
374.0669.
1016, 958, 767 cmÀ1 1H NMR (CDCl3): d=7.87 (d, J=8.4 Hz, 2H;
;
phenyl), 7.49–7.40 (m, 3H; phenyl), 3.91 (d, J=11.6 Hz, 1H; CH2), 3.69–
3.66 (m, 3H; CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.28–3.21 (m, 3H;
CH2), 1.74 (s, 3H; CH3), 1.63 (s, 6H; CH3), 1.56 ppm (s, 3H; CH3); 13C
NMR (CDCl3): d=180.5, 179.1, 178.9, 175.4, 168.7, 132.8, 131.6, 128.6,
128.5, 84.0, 83.8, 83.6, 83.5, 43.3, 43.0, 42.8, 40.7, 26.0, 25.8 (2C),
24.1 ppm; MS: [M+]: 518; HRMS: [M+1]+: calcd for C23H27N4O2S4:
Chem. Eur. J. 2007, 13, 3026 – 3038
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3035

T. Fukuyama et al.
General procedure for the preparation of difunctional thiol–carboxylic
acids 25, 27, and 32: A 10% aq. NaOH (2.2 equiv) solution was added to
a THF/MeOH (8:1, v/v) solution of N-Boc-thiazolidinone at 08C. The so-
lution was then stirred at room temperature for 15 min and acidified with
1n KHSO4 to pH 4–5 after being diluted with EtOAc. The aqueous
phase was extracted with EtOAc (10 mL) three times and the combined
organic extracts were dried with MgSO4, filtered, concentrated, and puri-
fied by column chromatography on acidic silica gel (hexane/EtOAc, 1:2)
to afford the desired thiol–carboxylic acid.
Cyclic novithiazoline (33): [a]2D5 =À223 (c=0.50 in CHCl3). IR (neat): n˜ =
2975, 2927, 2861, 1622, 1431, 1366, 1264, 1179, 1009, 907 cmÀ1 1H NMR
;
(CDCl3): d=3.75 (d, J=11.2 Hz, 9H; CH2), 3.22 (d, J=11.2 Hz, 9H;
CH2), 1.62 ppm (s, 27H; CH3); 13C NMR (CDCl3): d=175.7, 83.5, 43.3,
25.7 ppm; MS: [M++H]: 892; HRMS: [M++H]: calcd for C36H46N9S9
:
892.1362; found: 892.1318.
Monothiazoline methyl ester (6b): MeI (85.0 mL, 1.36 mmol) and K2CO3
(312 mg, 2.26 mmol) were added to DMF (5 mL) solution of 6a
a
(100 mg, 0.45 mmol) at 08C and the resulting mixture was stirred for 1 h.
The reaction mixture was washed with H2O (15 mL) four times after
being diluted with EtOAc. The combined organic extracts were dried
with MgSO4, filtered, concentrated, and purified by flash column chroma-
tography on silica gel (hexane/EtOAc, 4:1) to give 6b as a colorless oil
(108 mg, quantitative yield). [a]2D5 =À39.6 (c=0.5 in CHCl3). IR (neat):
Thiol–septithiazolinecarboxylic acid 25: Compound 25 was obtained in
81% yield from 20. [a]2D5 =À283.4 (c=0.40 in CHCl3). IR (neat): n˜ =
1
3335, 2980, 2932, 2860, 1717, 1164, 1011 cmÀ1; H NMR (CDCl3): d=3.77
(d, J=11.0 Hz, 1H; CH2), 3.70–3.63 (m, 6H; CH2), 3.53 (d, J=12.0 Hz,
1H; CH2), 3.45 (d, J=12.0 Hz, 1H; CH2), 3.29–3.20 (m, 6H; CH2), 3.08
(d, J=12.0 Hz, 1H; CH2), 1.93 (s, 3H; CH3), 1.69 (s, 3H; CH3),1.64 (s,
3H; CH3), 1.60 (s, 9H; CH3), 1.54 (s, 3H; CH3), 1.53 (s, 3H; CH3),
1.51 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3): d=180.3, 179.4, 178.5,
177.8, 175.1, 173.6, 169.7, 148.6, 84.4, 83.9, 83.8, 83.7, 83.5, 83.4, 67.4, 43.7,
43.1, 42.7, 42.6, 40.7, 37.1, 29.7, 28.0, 26.2, 26.1, 25.6, 25.1, 24.1, 23.4 ppm;
MS: [M++H]: 929; HRMS: [M++H]: calcd for C37H53N8O4S8: 929.1955;
found: 929.1964.
n˜ =2992, 2929, 2845, 1735, 1602, 1447, 1233, 1119, 956 cmÀ1 1H NMR
;
(CDCl3): d=7.86 (d, J=7.6 Hz, 2H; phenyl), 7.48–7.39 (m, 3H; phenyl),
3.91 (d, J=12.0 Hz, 1H; CH2), 3.82 (s, 3H; OCH3), 3.30 (d, J=10.8 Hz,
1H; CH2), 1.66 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=173.7, 168.2,
132.7, 131.4, 128.4, 128.3, 84.4, 52.8, 41.5, 23.8 ppm; MS: [M++H]: 236;
HRMS: [M++H]: calcd for C12H14NO2S: 236.0745; found: 236.0734.
General procedure for the preparation of oligothiazoline carboxamides:
procedure C: MeNH2 (20 equiv, 2.0m in THF) was added to a THF solu-
tion (THF/MeOH 2:1 was used in the case of hexi- and octithiazolines)
of oligothiazoline methyl ester. The resulting solution was stirred at room
temperature for 20–36 h. After removal of the solvent, the residue was
purified by flash column chromatography on silica gel (hexane/EtOAc,
2:1) to give the corresponding oligothiazoline carboxamide.
Thiol–terthiazolinecarboxylic acid 27: Compound 27 was obtained in
72% yield from 17. [a]2D5 =À202.2 (c=0.50 in CHCl3). IR (neat): n˜ =
1
3336, 2981, 2932, 2861, 1717, 1163, 1011 cmÀ1. H NMR (CDCl3): d=3.76
(d, J=12.0 Hz, 1H; CH2), 3.69 (d, J=12.0 Hz, 1H; CH2), 3.67 (d, J=
12.0 Hz, 1H; CH2), 3.52 (d, J=12.0 Hz, 1H; CH2), 3.44 (d, J=11.6 Hz,
1H; CH2), 3.26 (d, J=12.0 Hz, 1H; CH2), 3.21 (d, J=12.0 Hz, 1H; CH2),
3.09 (d, J=11.6 Hz, 1H; CH2), 1.94 (s, 3H; CH3), 1.60 (s, 3H; CH3), 1.56
(s, 6H; CH3), 1.51 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3): d=179.7,
178.3, 175.8, 173.7, 169.7, 148.6, 84.3, 83.8, 83.7, 83.3, 67.3, 43.6, 42.9, 40.8,
37.0, 27.9, 25.7, 24.9, 23.8, 23.3 ppm; MS: [M+]: 532; HRMS: [M+]: calcd
for C21H32N4O4S4: 532.1306; found: 532.1322.
Monothiazolinecarboxamide 6c: Compound 6c was obtained in 100%
yield from 6b. [a]2D5 =À162.2 (c=0.44 in CHCl3). IR (neat): n˜ =3407,
3354, 2977, 2928, 2864, 1667, 1524, 1447, 1256, 959, 768 cmÀ1 1H NMR
;
(CDCl3): d=7.86 (d, J=8.4 Hz, 2H; phenyl), 7.53–7.42 (m, 3H; phenyl),
6.93 (br, 1H; NH), 3.77 (d, J=12.0 Hz, 1H; CH2), 3.40 (d, J=12.0 Hz,
1H; CH2), 2.87 (d, J=4.8 Hz, 3H; NHCH3), 1.58 ppm (s, 3H); 13C NMR
(CDCl3): d=175.3, 168.8, 132.7, 131.8, 128.5, 128.3, 84.9, 41.5, 26.1,
24.7 ppm; MS: [M++H]: 235; HRMS: [M++H]: calcd For C12H15N2OS:
235.0905; found: 235.0904.
Thiol–bithiazolinecarboxylic acid (32): Compound 32 was obtained in
75% yield from 24. [a]2D5 =À131.9 (c=0.50 in CHCl3). IR (neat): n˜ =
1
3337, 2982, 2932, 2862, 1719, 1163, 1011 cmÀ1; H NMR (CDCl3): d=5.55
(br, 1H; NH), 3.74 (d, J=10.8 Hz, 1H; CH2), 3.69 (d, J=12.0 Hz, 1H;
CH2), 3.34 (d, J=12.0 Hz, 1H; CH2), 3.22 (d, J=11.6 Hz, 1H; CH2),
3.21–3.10 (m, 2H; CH2), 1.62 (s, 3H; CH3), 1.61 (s, 3H; CH3), 1.55 (s,
3H; CH3), 1.51 ppm (s, 9H; tert-butyl); 13C NMR (CDCl3): d=179.3,
176.3, 83.7, 59.3, 43.2, 40.9, 29.8, 28.1, 25.6, 23.9 ppm; MS: [M++H]: 434;
HRMS: [M++H]: calcd for C17H28N3O4S3: 434.1242; found: 434.1245.
Bithiazolinecarboxamide 10c: Compound 10c was obtained in quantita-
tive yield from 10a. [a]2D5 =À221.8 (c=0.5 in CHCl3). IR (neat): n˜ =3410,
3347, 2975, 2928, 2865, 1670, 1615, 1525, 1447, 1252, 1175, 1016, 957 cmÀ1
;
1H NMR (CDCl3): d=7.87 (d, J=7.6 Hz, 2H; phenyl), 7.50–7.41 (m, 3H;
phenyl), 6.76 (br, 1H; NH), 3.88 (d, J=10.8 Hz, 1H; CH2), 3.59 (d, J=
11.6 Hz, 1H; CH2), 3.42 (d, J=12.0 Hz, 1H; CH2), 3.23 (d, J=12.0 Hz,
1H; CH2), 2.88 (s, 1.5H; NHCH3), 2.87 (s, 1.5H; NHCH3), 1.72 (s, 3H;
CH3), 1.45 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=178.2, 175.3, 168.6,
132.7, 131.7, 128.5 (2C), 84.4, 83.9, 43.2, 41.3, 26.1, 25.9, 24.6 ppm; MS:
[M++H]: 334; HRMS: [M++H]: calcd for C16H20N3OS2: 334.1048;
found: 334.1046.
General procedure for the synthesis of cyclo-oligothiazolines: BOP-Cl
(2.0 equiv) and Et3N (4.0 equiv) were added to a solution of thiol–car-
boxylic acid in CH2Cl2 (4 mmolLÀ1) and the mixture was stirred at room
temperature for 18–20 h. The solution was then washed with 5% aq.
NaHCO3 and brine. The organic layer was separated and dried with
MgSO4, filtered, concentrated, and purified by flash column chromatog-
raphy on silica gel (hexane/EtOAc, 2:1) to give a mixture of products
generated by cyclo-oligomerization (27 provided a mixture of dimer and
trimer, and 32 provided a mixture of trimer and tetramer, respectively).
The mixture was then treated with neat TFA at room temperature for
20 min and evaporated to dryness. The residue was dissolved in benzene
and refluxed for 4 h, then evaporated to leave the crude products. The
crude products were purified by PTLC (hexane/EtOAc, 1:3) to give pure
cyclo-oligothiazolines (27 provided 30 and 31, and 32 provided 33 and 31,
respectively).
Terthiazolinecarboxamide 11c: Compound 11c was obtained in quantita-
tive yield from 11a. [a]2D5 =À382.4 (c=0.22 in CHCl3). IR (neat): n˜ =
3409, 3369, 2975, 2928, 2860, 1670, 1654, 1617, 1540, 1522, 1508, 1447,
1
1363, 1254, 1175, 1013, 958, 939, 769 cmÀ1; H NMR (CDCl3): d=7.87 (d,
J=8.0 Hz, 2H; phenyl), 7.48–7.41 (m, 3H; phenyl), 6.55 (br, 1H; NH),
3.91 (d, J=11.2 Hz, 1H; CH2), 3.68 (d, J=11.2 Hz, 1H; CH2), 3.59 (d,
J=10.8 Hz, 1H; CH2), 3.46 (d, J=10.8 Hz, 1H; CH2), 3.23 (d, J=
11.6 Hz, 1H; CH2), 3.22 (d, J=11.2 Hz, 1H; CH2), 2.86 (s, 1.5H;
NHCH3), 2.85 (s, 1.5H; NHCH3), 1.74 (s, 3H; CH3), 1.62 (s, 3H; CH3),
1.49 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=178.7, 178.0, 175.2, 168.6,
132.8, 131.6, 128.6, 128.5, 84.5, 84.0, 83.5, 43.2, 43.0, 41.2, 26.1, 25.9 (2C),
24.7 ppm; MS: [M++H]: 433; HRMS: [M++H]: calcd for C20H25N4OS3:
433.1190; found: 433.1199; elemental analysis calcd (%) for
C20H24N4OS3·0.25H2O: C 54.98, H 5.65, N 12.82; found: C 55.06, H 5.77,
N, 12.50.
Cyclic octithiazoline (30): [a]2D5 =À220 (c=0.50 in CHCl3). IR (neat): n˜ =
2974, 2927, 2861, 1621, 1432, 1365, 1268, 1178, 1009, 908 cmÀ1 1H NMR
;
(CDCl3): d=3.70 (d, J=10.8 Hz, 8H; CH2), 3.19 (d, J=10.8 Hz, 8H;
CH2), 1.63 ppm (s, 24H; CH3); 13C NMR (CDCl3): d=175.7, 83.1, 43.6,
25.2 ppm; MS: [M++H]: 793; HRMS: [M++H]: calcd for C32H41N8S8:
793.1220; found: 793.1205.
Cyclic dodecithiazoline (31): [a]2D5 =À283 (c=0.22 in CHCl3). IR (neat):
Quaterthiazolinecarboxamide 21c: Compound 21c was obtained in quan-
n˜ =2975, 2927, 2860, 1624, 1432, 1366, 1247, 1178, 1010, 907 cmÀ1
;
1H
titative yield from 21a according to the general procedure C. [a]D25
=
NMR (CDCl3): d=3.76 (d, J=10.8 Hz, 12H; CH2), 3.21 (d, J=10.8 Hz,
À364.2 (c=0.48 in CHCl3). IR (neat): n˜ =3410, 3369, 2978, 2930, 2861,
12H; CH2), 1.76 ppm (s, 36H; CH3); 13C NMR (CDCl3): d=176.6, 83.4,
1669, 1654, 1617, 1541, 1523, 1510, 1447, 1362, 1254, 1174, 1013, 959, 938,
43.0, 25.9 ppm; MS: [M+]: 1188; HRMS: [M+]: calcd for C48H60N12S12
:
769 cmÀ1 1H NMR (CDCl3): d=7.88 (d, J=6.8 Hz, 2H; phenyl), 7.49–
;
1188.1712; found: 1188.1730.
7.42 (m, 3H; phenyl), 6.73 (br, 1H; NH), 3.91 (d, J=12.0 Hz, 1H; CH2),
3036
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Chiral Thiazolines
FULL PAPER
3.71 (d, J=12.0 Hz, 1H; CH2), 3.67 (d, J=11.6 Hz, 1H; CH2), 3.57 (d,
J=12.0 Hz, 1H; CH2), 3.46 (d, J=12.0 Hz, 1H; CH2), 3.28–3.21 (m, 3H;
CH2), 2.86 (s, 1.5H; NHCH3), 2.85 (s, 1.5H; NHCH3), 1.74 (s, 3H; CH3),
1.63 (s, 3H; CH3), 1.57 (s, 3H; CH3), 1.45 ppm (s, 3H; CH3); 13C NMR
(CDCl3): d=178.6, 178.1, 175.2, 168.6, 132.8, 131.6, 128.6, 128.5, 84.5,
84.0, 83.6 (2C), 43.3, 43.1, 42.9, 41.2, 26.1, 25.9 (2C), 25.8, 24.6 ppm; MS:
[M+]: 531; HRMS: [M++H]: calcd for C24H30N5OS4: 532.1333; found:
Acknowledgements
We thank Drs. Ryoichi Ando and Yusaku Amno of Mitsubishi Pharma
Corporation for cytotoxicity measurements. We thank Dr. Yutaka
Matsuo, a group leader of the Nakamura Functional Carbon Cluster
Project, ERATO, Japan Science and Technology Agency, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, for the X-ray analysis and the Minis-
try of Education, Culture, Sports, Science, and Technology, Japan for fi-
nancial support.
532.1357; elemental analysis calcd (%) for C24H29N5OS4·0.75H2O:
C
51.91, H 5.21, N 10.52; found: C 52.43, H 5.22, N 10.27.
Hexithiazolinecarboxamide 22c: Compound 22c was obtained in quanti-
tative yield from 22a according to the general procedure C. [a]D25
=
À370.0 (c=0.28 in CHCl3). IR (neat): n˜ =3406, 2976, 2924, 2866, 1673,
[1] For reviews, see: a) R. J. Fitzmaurice, G. M. Kyne, D. Douheret,
J. D. Kilburn, J. Chem. Soc. Perkin Trans. 1 2002, 841; b) X. X.
Zhang, J. S. Bradshaw, R. M. Izatt, Chem. Rev. 1997, 97, 3313;
c) T. H. Webb, C. S. Wilcox, Chem. Soc. Rev. 1993, 22, 383; for rep-
resentative recent research articles on molecular recognition, see:
d) J. L. Sessler, D. An, W. S. Cho, V. Lynch, J. Am. Chem. Soc. 2003,
125, 13646.
[2] a) E. Izbicka, R. T. Wheelhouse, E. Raymond, K. K. Davidson,
R. A. Lawrence, D. Sun, B. E. Windle, L. H. Hurley, D. D. Von Hoff,
Cancer Res. 1999, 59, 639; b) J. Seenisamy, S. Bashyam, V. Gokhale,
H. Vankayalapati, D. Sun, A. Siddiqui-Jain, N. Streiner, K. Shin-
Yan, E. White, W. D. Wilson, L. H. Hurley, J. Am. Chem. Soc. 2005,
127, 2944.
1
1624, 1602, 1528, 1444, 1434, 1363, 1011 cmÀ1; H NMR (CDCl3): d=7.87
(d, J=7.2 Hz, 2H; phenyl), 7.49–7.40 (m, 3H; phenyl), 6.72 (br, 1H;
NH), 3.92 (d, J=12.0 Hz, 1H; CH2), 3.73–3.62 (m, 5H; CH2), 3.57 (d, J=
11.6 Hz, 1H; CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.29–3.20 (m, 4H;
CH2), 2.86 (s, 1.5H; NHCH3), 2.85 (s, 1.5H; NHCH3), 1.74 (s, 3H; CH3),
1.64 (s, 3H; CH3), 1.63 (s, 3H; CH3), 1.62 (s, 3H; CH3), 1.61 (s, 3H;
CH3), 1.45 ppm (s, 3H; CH3); 13C NMR (CDCl3): d=178.6, 178.5 (2C),
178.1, 175.2, 168.6, 132.9, 131.6, 128.6, 128.5, 84.5, 84.0, 83.7, 83.5, 43.3,
43.1, 43.0 (2C), 42.9, 41.2, 26.1, 25.9 (2C), 24.9, 24.6 ppm; MS: [M+]:
729; HRMS: [M++H]: calcd for C32H40N7OS6: 730.1618; found: 730.1647;
elemental analysis calcd (%) for C32H39N7OS6: C 52.57, H 5.51, N 13.41;
found: C 52.73, H 5.64, N 13.44.
[3] J. M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
VCH, Weinheim, 1995.
Octithiazolinecarboxamide 23c: Compound 23c was obtained in quanti-
tative yield from 23a according to the general procedure C. [a]D25
=
[4] J. Breitenbach, J. Boosfeld, F. Vogtle in Comprehensive Supramolec-
ular Chemistry, Vol. 2 (Eds.: J. L. Atwood, J. E. D. Davies, D. D.
MacNicol, F. Vogtle), Pergamon Press, Oxford, 1996, p. 29.
[5] a) S. Carmeli, R. E. Moore, G. M. L. Patterson, J. Am. Chem. Soc.
1990, 112, 8195; b) S. Carmeli, S. Paik, R. E. Moore, G. M. L. Patter-
son, W. Y. Yoshida, Tetrahedron Lett. 1993, 34, 6681.
À390.2 (c=0.20 in CHCl3). IR (neat): n˜ =3408, 2976, 2925, 2866, 1673,
1
1624, 1602, 1527, 1445, 1434, 1364, 1012 cmÀ1; H NMR (CDCl3): d=7.87
(d, J=7.2 Hz, 2H; phenyl), 7.49–7.40 (m, 3H; phenyl), 6.58 (br, 1H;
NH), 3.92 (d, J=12.0 Hz, 1H; CH2), 3.73–3.65 (m, 7H; CH2), 3.57 (d, J=
11.6 Hz, 1H; CH2), 3.46 (d, J=11.2 Hz, 1H; CH2), 3.29–3.20 (m, 6H;
CH2), 2.86 (s, 1.5H; NHCH3), 2.85 (s, 1.5H; NHCH3), 1.74 (s, 3H; CH3),
1.64 (s, 6H; CH3), 1.62 (s, 3H; CH3), 1.61 (s, 9H; CH3), 1.45 ppm (s, 3H;
CH3); 13C NMR (CDCl3): d=178.6, 178.5 (2C), 178.1, 175.2, 168.6, 132.9,
131.6, 128.6, 128.5, 84.5, 84.0, 83.7, 83.5, 43.3, 43.1, 43.0 (2C), 42.9, 41.2,
26.1, 25.9 (2C), 24.9, 24.6 ppm; MS: [M++H]: 928; elemental analysis
calcd (%) for C40H49N9OS8·0.5H2O: C 51.25, H 5.38, N 13.45; found: C
51.47, H 5.48, N 13.33.
[6] S. Carmeli, R. E. Moore, G. M. L. Patterson, Tetrahedron Lett. 1991,
32, 2593.
[7] a) R. Jansen, B. Kunze, H. Reichenbach, E. Jurkiewicz, G. Hun-
smann, G. Hofle, Liebigs Ann. Chem. 1992, 357; b) R. Jansen, D.
Schomburg, G. Hofle, Liebigs Ann. Chem. 1993, 701; c) B. Kunze, R.
Jansen, L. Pridzun, E. Jurkiewicz, G. Hunsmann, G. Hofle, H.
Reichenbach, J. Antibiot. 1993, 46, 1752.
[8] T. Fukuyama, L. Xu, J. Am. Chem. Soc. 1993, 115, 8049.
[9] F. S. Han, H. Osajima, M. Cheung, H. Tokuyama, T. Fukuyama,
Chem. Commun. 2006, 1757.
Bindingstudies of 30 by NMR titration using30 and ( R)-mandelic acid:
A CDCl3 solutions of 30 (1.5 mm, 0.50 mL) and (R)-mandelic acid
(18.8 mm, 0.7 mL) were prepared. After recording the NMR spectrum of
free 30, the (R)-mandelic acid solution was added to the solution of 30 in
portions (10, 10, 10, 10, 20, 20, 20, 20, 40, 40, 40, 80, 80, 80 mL, 10 mL cor-
responds to 0.25 equiv) and after each addition the NMR spectrum was
recorded at room temperature after 30 min of standing at room tempera-
ture. All the titrations were duplicated. A plot of the difference in chemi-
cal shifts of the thiazoline CH protons versus the ratio of mandelic acid
to 30 was curved.
[10] Examples of other approaches to the synthesis of linear arrays of
polythiazolines: for mirabazole, see: a) B. L. Kedrowski, C. H.
Heathcock, Heterocycles 2002, 56, 601; b) K. Akaji, N. Kuriyama, T.
Kiso, J. Org. Chem. 1996, 61, 3350; c) G. Pattenden, R. J. Boyce, Tet-
rahedron 1995, 51, 7313; d) M. A. Walker, C. H. Heathcock, J. Org.
Chem. 1992, 57, 5566; for tantazole, see: e) R. L. Parsons, C. H.
Heathcock, Synlett 1996, 1168; for thiangazole, see: f) K. Akaji, Tet-
rahedron 1999, 55, 10685; g) R. J. Boyce, G. C. Mulqueen, G. Patten-
den, Tetrahedron 1995, 51, 7321; h) P. Wipf, S. Vankatraman, J. Org.
Chem. 1995, 60, 7224; i) R. L. Parsons, C. H. Heathcock, J. Org.
Chem. 1994, 59, 4733.
Cytotoxicity: The in vitro cytotoxicity against three cancer cell lines, PC-
3, HCT-116, and HPAC, was evaluated by studying the inhibition of cell
growth rate using the WST-1 assay protocol. A human pancreatic ductal
carcinoma cell line HPAC was obtained from the American Type Culture
Collection (Manassas, VA). Human colorectal adenocarcinoma cell line
HCT-116 and human prostate adenocarcinoma PC-3 were obtained from
Dainippon Sumitomo Pharma Co., Ltd. (Osaka). Cell lines were cultured
in a 1:1 mixture of Dulbeccoꢁs modified Eagleꢁs medium and Hamꢁs F-12
medium (SIGMA) supplemented with 10% fetal bovine serum (ICN Bio-
medicals) in a humidified atmosphere of 95% O2 and 5% CO2 at 378C.
Cells were seeded at a concentration of 2”103 cells per well in the cul-
ture medium in 96-well microtiter plates. After incubation for 24 h, treat-
ment of the cells with the test compounds was started. After 72 h, 10 mL
WST-1 reagent (Dojindo Laboratories) was added to each well and the
plate was incubated at 378C for 3 h. Absorbance of the culture superna-
tant at 450 nm was measured using a microplate reader (Molecular Devi-
ces). The IC50 values were calculated from the concentration-response
curves as the concentration of the test compounds eliciting a decrease in
the measured absorbance equivalent to 50% of the vehicle group.
[11] Crystal data for 30·(CHCl3)2 at 153 K: C34H42Cl6N8S8, Mr 1031.99,
R
0.72”0.52”0.22 mm3, colorless crystal, triclinic, space group P1, a=
8.8700(4), b=12.0090(9), c=12.7400(9) Š, a=116.29(3), b=
88.97(5), g=101.44(5)8, V=1189(13) Š3, Z=1, final R1 =0.0472 for
3918 reflections on I>2s(I), R1 =0.0474, wR2 =0.1262 for all 3918
reflections. CCDC-290621 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
[12] For H and 13C NMR spectra of the macrocyclic compounds, see the
Supporting Information in reference [9].
[13] S. Kobayashi, S. Hidaka, Y. Kawamura, M. Ozaki, Y. Hayase, J. An-
tibiot. 1998, 51, 323.
[14] a) For selected reviews on artificial receptors for carboxylic acids,
see reference [1a]; for selected examples of the chiral recognition of
mandelic acid, see: b) J. Lin, H. C. Zhang, L. Pu, Org. Lett. 2002, 4,
Chem. Eur. J. 2007, 13, 3026 – 3038
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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T. Fukuyama et al.
3297; c) Y. S. Zheng, C. Zhang, Org. Lett. 2004, 6, 1189; d) Z. B. Li,
J. Lin, L. Pu, Angew. Chem. 2005, 117, 1718; Angew. Chem. Int. Ed.
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[16] a) F. Djedaini, S. Z. Lin, B. Perly, D. Wouessidjewe, J. Pharm. Sci.
1990, 79, 643; b) V. M. S. Gil, N. C. Oliveira, J. Chem. Educ. 1990,
67, 473.
[15] Extensive studies show evidence that multipoint interactions be-
tween a receptor and guest is key to obtaining good enantiomeric
recognition because multipoint interactions increase the rigidity of
the complex. For a detailed review, see p. 3318 of reference [1b].
[17] M. Herrrmann, J. Ehrler, H. Kayser, A. Rindlisbacher, G. Hçfle,
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Received: October 10, 2006
Published online: February 7, 2007
3038
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