Enantioselective synthesis of cyclic thioureas via mannich reaction and concise synthesis of highly optically active methylthioimidazolines: Discovery of a more potent antipyretic agent

Article abstract of DOI:10.1002/adsc.201100288

Drug lead synthesis by the rapid construction of chiral molecular complexity around the biologically relevant framework using a highly efficient strategy is a key goal of organic synthesis. Herein, a highly efficient and convenient strategy that allows th

Full text of DOI:10.1002/adsc.201100288

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DOI: 10.1002/adsc.201100288
Enantioselective Synthesis of Cyclic Thioureas via Mannich
Reaction and Concise Synthesis of Highly Optically Active
Methylthioimidazolines: Discovery of a More Potent
Antipyretic Agent
Xianxing Jiang,a,b,c Yiqing Wang,a,c Gen Zhang,a Dan Fu,a Futing Zhang,a
Ming Kai,a and Rui Wanga,b,*
a
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, State Key Laboratory of Applied Organic
Chemistry, Institute of Biochemistry and Molecular Biology, Lanzhou University, Lanzhou, Peopleꢀs Republic of China
Fax : (+86)-931-891-1255; e-mail: wangrui@lzu.edu.cn
State Key Laboratory of Chiroscience, Department of Applied Biology and Chemical Technology, The Hong Kong
b
Polytechnic University, Kowloon, Hong Kong
E-mail: bcrwang@polyu.edu.hk
These authors contributed equally to this work
c
Received: April 17, 2011; Published online: June 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100288.
Abstract: Drug lead synthesis by the rapid construc- promising antipyretic activity in the development of
tion of chiral molecular complexity around the bio- neuroinflammation through preliminary biological
logically relevant framework using a highly efficient studies. Additionally, to gain a better understanding
strategy is a key goal of organic synthesis. Herein, a of the structural stability-activity relationships, ex-
highly efficient and convenient strategy that allows plicit molecular dynamics (MD) simulations in water
the rapid synthesis of highly optically active methyl- at room temperature and at body temperature were
thioimidazolines through the novel rosin-derived investigated.
thioACHTUNGTRENNUNGurea-catalyzed asymmetric synthesis of cyclic thi-
oureas with high levels of enantio- and diastereose-
lectivity (up to 99% ee, and 20:1 dr) via Mannich re- Keywords: antipyretic agents; asymmetric synthesis;
action is described fior the first time. Several of the methylthioimidazolines; tertiary amine-thiourea cat-
new methylthioimidazolines showed extremely alysts
Introduction
strategy to prevent and treat brain diseases closely as-
sociated with neuroinflammation, such as multiple
Drug-lead organic synthesis, in particular the highly sclerosis[3a] and Alzheimerꢀs disease.[3b] Epidemiologi-
enantioselective construction of target-oriented chiral cal and clinical evidence[4] suggests that long-term use
molecular complexity, is recognized as one of the of anti-inflammatory drugs may impede the onset and
most challenging subjects for synthetic chemists[1] and, slow the progression of Alzheimerꢀs disease. For these
furthermore, searching for a proper efficient biologi- reasons, we recently first presented our contribution
cal model for the screening evaluation of structurally on the successful synthesis of a new kind of spirooxa-
diverse chiral targets is a difficult task. Therefore, al- zoline, which revealed promising biological activity
though there has been great demand, the develop- with an antipyretic action against the development of
ment of efficient synthetic methodologies in this area neuroinflammation.[5] Nevertheless, this significant re-
of research and finally their contribution to the dis- search remains a much less developed field, and cata-
covery of new therapeutic agents still remains scarce lytic enantioselective synthesis and preliminary bio-
to date. Antipyretic drugs against neuroinflamma- logical studies would still be highly valuable in both
tion[2] are an important but expensive class of clinical pharmaceutical and organic chemistry. Inspired by
therapeutic agents, which can be used as a therapeutic our recent elegant advances in this field, we ques-
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Scheme 1. Strategy for the synthesis of chiral methylthioimidazolines by tertiary amine-thiourea-cataylzed reactions and sim-
ilar cores in spirooxazolines.
tioned whether other structurally similar molecules or
analogues such as methylthioimidazoline[6] (A,
Scheme 1) would show more powerful antipyretic ac-
tivity to thereby provide an opportunity to discover
new antipyretic agents. In this text, we wish to present
our results on this topic.
Results and Discussion
During our recent research interests in the catalytic
enantioselective synthesis of biological and pharma-
ceutical precedents by using rosin-derived thiourea
catalysts[7,8] and to further expand the synthetic utility
of this conceptually new catalytic system, we envi-
sioned that the optically active methylthioimidazoline
A could analogously be obtained through methylation
Figure 1. Structure of thiourea catalysts.
of the cyclic thiourea C, which might be generated via
a catalytic enantioselective intramolecular Mannich[9]
cyclization reaction of a-isothiocyanato imides[10] to well in the reaction owing to its excellent structural
N-tosylimines in the presence of a tertiary amine-thio- backbone and well-defined stereocenters. To explore
urea[11] (Scheme 1). To the best of our knowledge, to the efficacy of rosin-derived tertiary amine-thiourea
date, the catalytic asymmetric synthesis and prelimi- system for the proposed Mannich cyclization process,
nary biological studies of highly enantiomerically en- the model reaction of isothiocyanate 1a with N-tosyli-
riched methylthioimidazolines have not been reprot- mine 2a was performed in toluene at room tempera-
ed, and thus remains an important challenge. We first ture in the presence of 5.0 mol% of ligand loading
reveal herein an asymmetric synthetic approach to (Table 1). The results showed that tertiary amine-thio-
such compounds and their extremely promising anti- ureas 3d–3f gave poor results in terms of yield and
pyretic activity in the development of neuroinflamma- stereochemical outcome (entries 1–3). Interestingly, a
tion through preliminary biological studies.
significant enhancement of yield and stereoselectivity
Subsequently, our attention was especially focused was achieved when using 3g (93% yield, 9:1 dr and
on the catalytic highly enantioselective synthesis of 96% ee, entry 4), and the further solvent optimization
cyclic thioureas because several very practical tertiary indicated that a remarkable decrease of ee values was
amine-thiourea catalysts 3a–3c (Figure 1) proved to observed in CH2Cl2, Et2O and CHCl3 while the reac-
be inefficient for this catalytic asymmetric reaction in tions afforded the products with high yields (en-
previous studies reported by Seidel[10b] and Zhong[10c] tries 6–8). Gratifyingly, we further lowered the tem-
independently. It is important to note that, except for perature to À158C, and better enantioselectivity was
the first reported example using a metallic catalyst,[10e] obtained without a significant decrease in yield (97%
almost the same small molecules were employed as ee and 90% yield, entry 9).
exclusive efficient catalysts in the aforementioned two
organocatalytic versions. Even so, we still believe that with respect to the synthesis of a variety of cyclic
our rosin-derived thiourea catalyst might perform thioureas under the optimized reaction conditions
We then investigated the generality of the protocol
AHCTUNGTRENNUNG
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Enantioselective Synthesis of Cyclic Thioureas via Mannich Reaction
Table 1. Catalyst screening and optimization of reaction con-
Table 2. Cyclic thioureas formed by rosin-derived tertiary
ditions.[a]
amine-thiourea-catalyzed asymmetric Mannich reaction.[a]
Entry Catalyst Substrate Yield [%][b] dr[c] ee [%][d]
1
2
3
4
3d
3e
3f
3g
3g
3g
3g
3g
3g
1a
1a
1a
1a
1b
1a
1a
1a
1a
(4a) 37
(4a) 40
(4a) 49
(4a) 93
(4b) 89
(4b) 92
(4a) 79
(4a) 91
(4a) 90
4:1
4:1
5:1
9:1
4:1
5:1
5:1
5:1
9:1
33
34
67
88
80
51
42
65
97
5
6[e]
7[f]
8[g]
9[h]
[a]
Unless noted otherwise, the reaction was carried out with
1 (0.20 mmol) and 2a (0.30 mmol) in toluene (1.5 mL)
for 12 h at room temperature.
[b]
[c]
[d]
Isolated yield of the mixture of diasteromers.
1
Determined by H NMR.
The ee values of the major diastereomer were deter-
mined by HPLC, and the configuration was assigned by
comparison of HPLC data and X-ray crystal data of
TID-1.
In CH2Cl2 (1.0 mL).
In Et2O (1.0 mL).
In CHCl3 (1.0 mL).
The reaction was performed for 18 h at À158C .
[e]
[f]
[a]
[g]
[h]
Unless noted, the reaction was carried out with isothio-
cyanates (0.20 mmol) and N-tosylimines (0.30 mmol) in
toluene (1.5 mL) at À158C in the presence of 5.0 mol%
of 3g. For experimental details, see the Supporting Infor-
mation.
The configuration was assigned by comparison of HPLC
data and X-ray crystal data of TID-1.
(Table 2). It is seen that a variety of aromatic N-tosyl-
ACHTUNGTRENNUNGimines bearing various types of substituents under-
[b]
[c]
went the reaction to afford the desired products with
excellent enantioselectioselectivities (91%–99% ee) in
good to high diastereoselectivities (6:1–20:1 dr) and
yields (79–94%, entries 1–12). Encouraged by the out-
standing results achieved above, we decided to carry
out some more challenging studies, such as the con-
struction of spirocyclic[12] thioureas considering their
potential versatility. Gratifyingly, although low diaste-
reoselectivities were observed in phenyl and ortho-F-
substituted aromatic N-tosylimines (entries 13 and
14), in general, the catalytic system also proved to be
efficient for the enantioselective construction of spiro-
cyclic thioureas, again leading to high yields (81–
90%) and excellent enantioselectivities (90–96% ee,
entries 13–17).
Isolated yield of the mixture of diasteromers.
[d]
[e]
1
Determined by H NMR and chiral HPLC.
The ee values of the major diastereomer were deter-
mined by HPLC.
The proposed possible model to account for the
high enantioselectivity is shown in Figure 2. In light of
the experimental results described above and recent
studies,[5] the tertiary amine-thiourea would act in a
bifunctional fashion. The a-carbon atom of isothio- Figure 2. Proposed model of the reaction transition state.
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cyanate could be activated via enolate anion by an in-
teraction between the neighboring tertiary amine
moiety of the catalyst and isothiocyanate, alongside
which the N-tosylimine is fixed and activated by the
two thiourea hydrogen atoms through weak hydrogen
bonds. Subsequently the attack of the incoming nucle-
ophile to the re-face of N-tosylimine takes place
(attack on the si-face of the N-tosylimine is restricted
by the quinine scaffold of the catalyst), which is con-
sistent with the experimental results. In previous stud-
ies,[8c,d] we also tried to explain the role of the rosin
amine moiety of the catalyst for obtaining high enan-
tioselectivities and diastereoselectivities by carrying
out reaction with catalysts having different configura-
tion of the chiral scaffold moiety in the catalyst. The
investigation proved that the two chiral moieties of
the thiourea are mutually reinforcing for the high effi-
cacy of the catalyst. The catalytic activity depends
mainly on the remaining chiral scaffold moiety of the
thiourea (the inherent property of the stereochemical
structure of the dehydroabietic amine moiety of the
thiourea) and also on the suitable matching of the ste-
reochemical features of the remaining quinine scaf-
fold moiety. The stereochemical control of the reac-
tion is mainly provided by the quinine moiety of the
thiourea. In addition, the excellent structural back-
bone and well-defined stereocenters of the dehydro-
Scheme 2. Synthesis of biologically active chiral methylthio-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGabietic amine moiety of 3g also have an important
effect on the high enantioselectivity for the formation
of adduct.
In view of the next preliminary biological evalua-
tion, several synthesis-oriented optically active meth-
ylthioimidazolines were synthesized under the asym-
metric protocol established (Scheme 2). A variety of
substituted methylthioimidazolines with different
steric and electronic parameters (TID-1 to TID-5)
were smoothly formed with excellent enantioselectivi-
ties (90% to 99% ee) in yields ranging from 87% to
93%. With these novel chiral molecules in hand, the
aim of the present report was to investigate their anti- Figure 3. Antipyretic activity of TID-1 and TID-2 in neuro-
inflammation. The change of body temperature induced by
LPS in the absence or presence of TID-1 or TID-2 injected
into the third ventricle at 240.0 min in mice. The rectal tem-
perature was recorded after injection of saline, LPS, or the
co-application of LPS and TID-1 or TID-2. Each data point
represents the meanÆstandard error of the mean from ex-
periments conducted on 6–8 mice per group. Points labeled
with # were significantly different (p<0.05) from the corre-
sponding points for LPS alone; * significantly different from
saline (p<0.05) (For experimental details, see the Support-
pyretic activity on the fever provoked by intracere-
broventricular (icv) injection of lipopolysaccharide
(LPS) a component of the outer membrane of Gram-
negative bacteria. The injection of LPS directly into
the brain has been recognized as an animal model for
the study of neuroinflammation.[13] (Figure 3). Excit-
ingly, several of the compounds, including TID-1 and
TID-2, were found to attenuate the fever caused by
the icv injection of LPS in a dose-dependent manner.
As shown in Figure 3, the fever induced by LPS ing Information).
(125.0 ng) is significantly reduced by coinjection of
TID-1 or TID-2 (20.0 nmol) (P<0.05) at 240 min.
Compared to saline, the central injection of TID-1 or
TID-2 (20.0 nmol) did not change the body tempera- action to inflammation. The pivotal role of these
ture. In addition, TID-1 or TID-2 (2.0 and 10.0 nmol) methylthioimidazolines in the control of the process
slightly, but not significantly, decreased LPS-induced of neuroinflammation may help to prevent and treat
fever at 240 min. Fever is part of the acute-phase re- neuroinflammation diseases.
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Enantioselective Synthesis of Cyclic Thioureas via Mannich Reaction
formations were observed at temperatures of 300 K
and 315 K. The results obtained suggest that the sta-
bility of the conformation depends on the overall in-
teraction energy involved in the electrostatic force
and Van der Waals force.[14] In addition, the stacking
interactions[15] may also play an important role in sta-
bilizing the orientation of TID-1 (for details, see the
Supporting Information).
Conclusions
In conclusion, we have disclosed the synthesis of
highly optically active methylthioimidazolines through
the novel rosin-derived thiourea-catalyzed asymmetric
synthesis of cyclic thioureas with high levels of enan-
tio- and diastereoselectivity (up to 99% ee, and 20:1
dr) via Mannich reaction. Several of the new methyl-
thioimidazolines showed extremely promising antipy-
retic activity in the development of neuroinflamma-
tion through preliminary biological studies. Addition-
ally, to gain a better understanding of the structural
stability-activity relationships, the explicit molecular
dynamics (MD) simulations in water at room temper-
ature and body temperature were investigated.
Experimental Section
General Procedure of the Synthesis
All reactions were carried out under an argon atmosphere
condition unless otherwise noted and solvents were dried ac-
cording to established procedures. Reactions were moni-
tored by thin layer chromatography (TLC), column chroma-
tography purifications were carried out using silica gel
GF254. Proton nuclear magnetic resonance (1H NMR) spec-
tra were recorded on a Bruker 300 MHz spectrometer in
CDCl3 unless otherwise noted and carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on a Bruker
300 MHz spectrometer in CDCl3 using tetramethylsilane
(TMS) as internal standard unless otherwise noted. Data are
presented as follows: chemical shift, integration, multiplicity
(br=broad, s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, cm=complex multiplet) and coupling con-
stant in Hertz (Hz). Infrared (IR) spectra were recorded on
an FT-IR spectrometer. Optical rotations were recorded on
a Perkin–Elmer 341 polarimeter. HR-MS were measured
with an APEX II 47e mass spectrometer. Melting points
were measured on an XT-4 melting point apparatus and are
uncorrected. The ee values determination was carried out
using chiral high-performance liquid chromatography
(HPLC) with a Daicel Chiracel AD-H column on a Waters
apparatus with a 2996 UV-detector and the dr values were
Figure 4. X-ray crystal structure of TID-1 and the conforma-
tions obtained after explicit MD simulations in water at
300 K and 315 K. The atoms C, N, S, O and H are colored in
gray with 90%, 70%, 50%, 30%, 10%. Figure was drawn by
means of PyMol (A colored version of this figure is shown
in the Supporting Information).[16]
In light of the potent biological activities in vivo,
we sought to determine the conformation of TIDs in
a simulated body environment which is surrounded
by water at 315 K. To investigate the explicit confor-
mation of the TIDs in water, the crystal 3D model of
TID-1 (Figure 4) was embedded in a water box and
we performed 20.0 ns unrestrained molecular dynam-
ics (MD) simulations at 300 K (body temperature)
and 315 K (room temperature, compared with the
body environment). The time evolutions of the total
energy and RMSD (root mean square deviation) of
TID-1 were analyzed to evaluate the stability of each
system. The average structure of the last 5.0 ns trajec-
tory was considered as the typical structure of the
TID-1 model. Finally, two identical structures of the
TID-1 at different temperatures were obtained (all
atom RMSD=0.026). During explicit MD simulations
in water, a noteworthy phenomenon is that TID-1 ex-
1
determined by 300 Hz H NMR.
General Procedure for the Biological Studies
Male Kunming mice weighting 27–30 g were used. The ex-
hibited a strong structural stability and identical con- periments were performed between 10:00 and 17:00. All
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mice were housed one per cage in a room maintained at
22Æ0.58C and relative humidity of 52Æ2% with free access
to food and water. The mice were placed in the specially de-
signed restraining device as described by Rosow et al., with
their tails taped lightly to horizontal posts.[17] Rectal temper-
ature was measured with a thermistor probe (Machine
Equipment Corporation of GaoBeiDian, China) inserted to
2212, 1915, 1735, 1622, 1539, 1472, 1363, 1292, 1234, 11362,
1032, 911, 824, 732 cmÀ1; HR-MS (ESI): m/z=651.4079,
calcd for C41H54N4OS+H+: 651.4091; D=1.8 ppm.
General Procedure for the Organocatalytic
Asymmetric Synthesis of Cyclic Thioureas via
a depth of 2.5 cm into the rectum, which was linked to a re- Mannich Reaction of Isothiocyanate (1a) with N-
corder system (model BL-420E+, Taimeng Technology Cor-
poration of Chengdu, China). The icv administration into
the third ventricle was performed following the method de-
scribed by Francꢂs et al.[18] The drugs were coinjected to in-
vestigate whether the fever of LPS could be antagonized by
TIDs. Body temperature was recorded before injection and
then at 120, 180, 240 and 300 min after icv in the third ven-
tricle or various treatments and controls. Changes in body
temperature after injection and before drug administration
were calculated for each animal. The time courses of change
in body temperature of mice subjected to different treat-
ments are shown in Figure 3. Data are given as means Æ
S.E.M. One-way ANOVA followed by the Bonferroniꢀs
post-hoc test was used to establish statistical significance; a
probability level of P<0.05 was considered to be significant.
Tosylimines
To a stirred solution of 3g (0.006 mmol, 3.0 mol%) and N-
tosylimine (0.30 mmol) in dry toluene (1.5 mL), isothiocya-
nate 1a (0.20 mmol) was added under argon, The solution
was stirred at À158C for 18–36 h. After the reaction was
completed (monitored by TLC), the resulting mixture was
concentrated under reduced pressure and the residue was
purified through column chromatography on silica gel to
give the optical pure products (see Supporting Information).
4,4-Dimethyl-3-[(4S,5R)-5-phenyl-2-thioxo-1-tosylimida-
zolidine-4-carbonyl]oxazolidin-2-one (4a): Colorless nee-
dles; [a]20: À74 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3):
1
d=7.54–D7.52 (d, J=8.4 Hz, 2H), 7.36–7.34 (m, 5H), 7.22
(br, 1H), 7.11–7.09 (d, J=8.1 Hz, 1H), 6.24–6.23 (d, J=
1.8 Hz, 1H), 4.89 (d, J=1.8 Hz, 1H), 4.13 (s, 2H), 2.35 (s,
3H), 1.62 (s, 3H), 1.58 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=178.9, 167.2, 154.2, 144.8, 138.3, 134.8, 129.5, 129.1, 129.0,
128.7, 127.0, 76.1, 66.0, 64.7, 61.4, 24.6, 24.5, 21.6. IR: n=
3381, 2976, 1779, 1601, 1470, 1397, 1310, 1244, 1168, 1094,
1046, 761, 698, 670, 578, 544 cmÀ1; ESI-MS: m/z=474 [M+ ].
Major diastereomer: ee was determined by HPLC analysis
(Chiralcel AD-H, i-PrOH/hexane=30/70, 1.0 mLminÀ1,
245 nm): retention times tminor =12.99 min, tmajor =18.93 min,
ee 97%.
The Experiments of Dynamics (MD) Simulations
The crystal 3D model of TID-1 was embedded in a water
box. The topologies were generated by PRODRG. MD sim-
ulations were performed with the GROMACS 4.5.1 package
employing NPT and periodic boundary conditions. A modifi-
cation of GROMOS96 force field is applied for the system.
A twin cutoff of 10 ꢃ was used for the short-range interac-
tion and a cutoff of 12 ꢃ was used for the Lennard–Jones in-
teraction. The Particle Mesh Ewald (PME) algorithm was
used for the calculation of electrostatic contributions to en-
ergies and forces. Bond length was constrained using the
LINCS algorithm. Two systems were coupled to a tempera-
ture bath at 300 K and 315 K, with a coupling constant of
0.1 ps. Isotropic coupling with time constant of 1.0 ps was
applied to keep the pressure at 1.0 bar. The systems were
first energy minimized using the steepest descent integrator
for about 6000 steps. Then a 20.0 ns simulation was per-
formed with a time step of 2.0 fs. The time evolutions of the
total energy and RMSD of TID-1 were analyzed to evaluate
the stability of each system.
4,4-Dimethyl-3-[(4S,5R)-5-(naphthalen-1-yl)-2-thioxo-1-
tosylimidazolidine-4-carbonyl]oxazolidin-2-one (4b): White
solid; [a]2D0: À30 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3):
1
d=7.95–7.86 (m, 5H), 7.58–7.44 (m, 4H), 7.33 (br, 1H)
7.23–7.17 (m, 2H), 4.61 (s, 1H), 4.08 (s, 2H), 2.41 (s, 3H),
1.66 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
178.3, 167.3, 154.1, 145.0, 134.8, 134.1, 129.6, 129.4, 128.9,
127.1, 126.1, 125.7, 123.7, 121.8, 76.1, 64.9, 62.3, 61.4, 24.5,
24.4, 21.7; IR: n=3368, 3041, 1797, 1702, 1488, 1411, 1369,
1267, 1218, 1170, 1121, 1088, 726, 570 cmÀ1; anal. calcd. for
C26H25N3O5S2: C 59.64, H 4.81, N 8.02; found: C 59.84, H
4.66, N, 8.12. Major diastereomer: ee was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane=30/70,
Thiourea catalyst (3 g) was synthesized according to the
1.0 mLminÀ1, 245 nm): retention times
major =13.56 min, ee 91%.
4,4-Dimethyl-3-[(4S,5R)-5-(naphthalen-2-yl)-2-thioxo-1-
tminor =12.02 min,
literature procedures.[8]
t
1-{[(1R,4aS,10aR)-7-Isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,
10,10a-octahydrophenanthren-1-yl]methyl}-3-{[(S)-(6-meth-
oxyquinolin-4-yl)-[(2S,4S,8R)-8-vinylquinuclidin-2-yl]meth-
yl}thiourea (3g): [a]D20: À70 (c 1.0, CHCl3); mp 1638C.
1H NMR (300 MHz, DMSO-d6): d=8.67 (s, 1H), 7.89–7.92
(m, 2H), 7.37–7.44 (m, 2H), 7.10–7.13 (d, J=8.1 Hz, 1H),
6.83–6.95 (m, 2H), 5.72–5.83 (m, 2H), 4.87–4.98 (m, 2H),
3.90 (s, 3H), 3.55–3.58 (d, J=10.5 Hz, 1H), 3.04–3.14 (m,
4H), 2.75–2.80 (m, 3H), 2.51–2.58 (m, 2H), 2.22 (m, 2H),
1.81 (br, 1H), 1.38–1.54 (m, 7H), 1.15–1.18 (m, 11H), 1.09
(m, 3H), 0.78 (m, 4H); 13C NMR (75 MHz, DMSO-d6): d
157.9, 148.5, 148.1, 145.9, 145.2, 142.9, 135.7, 132.2, 128.9,
127.4, 125.0, 124.5, 122.2, 115.2, 104.2, 56.6, 56.3, 45.1, 41.8,
38.9, 38.4, 37.9, 36.8, 33.9, 30.5, 28.4, 28.1, 26.6, 26.1, 25.1,
24.9, 21.8, 19.8, 19.6, 19.2; IR: n=3271, 3069, 2931, 2866,
tosylimidazolidine-4-carbonyl]oxazolidin-2-one (4c): White
solid; [a]2D0: +35 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.83–7.78 (m, 4H), 7.55–7.51 (m, 4H), 7.38–7.35
(d, J=8.4 Hz, 2H), 7.21 (s, 1H), 6.98–6.95 (d, J=8.1 Hz,
1H), 6.45–6.44 (d, J=1.8 Hz, 1H), 4.94–4.93 (d, J=2.1 Hz,
1H), 4.13 (s, 2H), 2.29 (s, 3H), 1.64 (s, 3H), 1.61 (s, 3H);
13C NMR (75 MHz, CDCl3): d=179.0, 167.2, 154.2, 114.8,
135.4, 134.8, 134.4, 133.4, 133.0, 129.4, 128.6, 128.3, 127.7,
126.8, 126.7, 123.8, 76.1, 66.1, 64.7, 61.4, 24.6, 24.5, 21.6; IR:
n=3366, 3038, 1802, 1711, 1486, 1411, 1368, 1256, 1210,
1172, 1124, 1098, 745, 571 cmÀ1
C26H25N3O5S2: C 59.64, H 4.81, N 8.02; found: C 59.75, H
4.70, N 8.16. Major diastereomer: ee was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane=30/70,
;
anal. calcd. for
1792
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ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1787 – 1796

Enantioselective Synthesis of Cyclic Thioureas via Mannich Reaction
1.0 mLminÀ1, 245 nm): retention times
major =18.98 min, ee 98%.
3-[(4S,5R)-5-(4-Fluorophenyl)-2-thioxo-1-tosylimidazoli-
t
minor =16.49 min,
hexane=30/70, 1.0 mLminÀ1, 245 nm): retention times
t
tminor =11.63 min, tmajor =13.77 min, ee 97%.
3-[(4S,5R)-5-(2-Chlorophenyl)-2-thioxo-1-tosylimidazoli-
dine-4-carbonyl]-4,4-dimethyloxazolidin-2-one (4d): Color-
dine-4-carbonyl]-4,4-dimethyloxazolidin-2-one (4h): Color-
1
1
less needles; [a]2D0: À17 (c 1.0, CHCl3). H NMR (300 MHz,
less needles; [a]2D0: +12 (c 1.0, CHCl3). H NMR (300 MHz,
CDCl3): d=7.47–7.44 (d, J=7.5 Hz, 2H), 7.38–7.36 (m, 2H),
7.22–7.06 (m, 5H), 6.65 (d, J=2.1 Hz, 1H), 4.82–4.81 (d, J=
1.8 Hz, 1H), 4.13 (s, 2H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (s,
3H); 13C NMR (75 MHz, CDCl3): d=178.4, 166.8, 161.1,
154.3, 145.0, 134.7, 130.6, 129.5, 128.9, 124.9, 124.9, 116.0,
115.7, 76.1, 64.0, 61.3, 60.5, 24.5, 21.7; IR: n=3344, 3041,
2969, 1748, 1611, 1509, 1370, 1227, 1094, 841, 756, 728, 682,
591, 572 cmÀ1; anal. calcd. for C22H22FN3O5S2: C 53.75, H
4.51, N 8.55; found: C 53.61, H 4.40, N 8.66. Major diaste-
reomer: ee was determined by HPLC analysis (Chiralcel
AD-H, i-PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): re-
tention times tminor =11.55 min, tmajor =12.62 min, ee 96%.
3-[(4S,5R)-5-(4-Chlorophenyl)-2-thioxo-1-tosylimidazoli-
dine-4-carbonyl]-4,4-dimethyloxazolidin-2-one (4e): Color-
CDCl3): d=7.62–7.59 (d, J=8.4 Hz, 2H), 7.34–7.30 (m, 4H),
7.17–7.14 (d, J=8.1 Hz, 2H), 7.11 (br, 1H), 6.20 (d, J=
1.2 Hz, 1H), 4.84–4.83 (d, J=1.8 Hz, 1H), 4.15 (s, 2H), 2.39
(s, 3H), 1.64 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=178.9, 167.1, 154.2, 145.1, 136.9, 135.1, 134.7,
129.4, 129.3, 128.8, 128.4, 76.2, 65.4, 64.5, 61.4, 24.7, 24.5,
21.7; IR: n=3346, 3052, 2971, 1720, 1641, 1515, 1374, 1227,
1097, 840, 759, 682, 588, 570 cmÀ1
; anal. calcd. for
C22H22ClN3O5S2: C 52.01, H 4.36, N 8.27; found: C 52.22, H
4.43, N 8.08. Major diastereomer: ee was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane=30/70,
1.0 mLminÀ1, 245 nm): retention time: tmajor =19.77 min, ee
99%.
4,4-Dimethyl-3-[(4S,5R)-2-thioxo-5-p-tolyl-1-tosylimidazo-
1
less needles; [a]2D0: +55 (c 1.0, CHCl3). H NMR (300 MHz,
lidine-4-carbonyl]oxazolidin-2-one (4i): Colorless solid; [a]2D0:
1
CDCl3): d=7.60–7.57 (d, J=8.4 Hz, 2H), 7.36–7.27 (m, 5H),
7.16–7.13 (d, J=8.4 Hz, 2H), 6.12 (d, J=1.2 Hz, 1H), 4.89
(d, J=1.8 Hz, 1H), 4.14 (s, 2H), 2.38 (s, 3H), 1.62 (s, 3H),
1.56 (s, 3H); 13C NMR (75 MHz, CDCl3): d=179.2, 167.3,
154.2, 145.1, 136.8, 135.0, 134.7, 129.3, 129.2, 128.8, 128.5,
76.1, 65.6, 64.4, 61.4, 24.6, 24.4, 21.7. IR: n=3348, 3046,
2972, 1746, 1640, 1510, 1374, 1225, 1098, 841, 759, 727, 679,
588, 570 cmÀ1; anal. calcd. for C22H22ClN3O5S2: C 52.01, H
4.36, N 8.27; found: C 52.31, H 4.39, N 8.06. Major diastereo-
mer: ee was determined by HPLC analysis (Chiralcel AD-
H, i-PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): retention
time tmajor =14.62 min, ee 99%.
3-[(4S,5R)-5-(4-Bromophenyl)-2-thioxo-1-tosylimidazoli-
dine-4-carbonyl]-4,4-dimethyloxazolidin-2-one (4f): Color-
less solid; [a]2D0: +18 (c 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): d=7.62–7.59 (d, J=8.4 Hz, 2H), 7.48–7.46 (d, J=
8.4 Hz, 2H), 7.24–7.21 (d, J=8.4 Hz, 2H), 7.17–7.14 (d, J=
8.4 Hz, 2H), 6.17 (d, J=1.2 Hz, 1H), 4.84 (d, J=1.8 Hz,
1H), 4.15 (s, 2H), 2.39 (s, 3H), 1.64 (s, 3H), 1.59 (s, 3H);
13C NMR (75 MHz, CDCl3): d=179.0, 167.1, 154.2, 145.1,
137.3, 134.7, 132.2, 129.4, 128.8, 128.7, 123.3, 76.2, 65.5, 64.5,
61.4, 24.7, 24.5, 21.7; IR: n=3357, 3059, 2988, 1794, 1705,
1489, 1394, 1264, 1214, 1168, 1114, 755, 725, 688, 614,
570 cmÀ1; anal. calcd. for C22H22BrN3O5S2: C 47.83, H 4.01,
N 7.61; found: C 48.03, H 4.18, N 7.54. Major diastereomer:
ee was determined by HPLC analysis (Chiralcel AD-H, i-
PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): retention
times tmajor =15.40 min, tminor =20.80 min, ee 98%.
À67 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): d=7.58–
7.55 (d, J=8.4 Hz, 2H), 7.25–7.16 (m, 5H), 7.12–7.10 (d, J=
8.4 Hz, 2H), 6.21 d, J=1.2 Hz, 1H), 4.87 (d, J=1.8 Hz, 1H),
4.13 (s, 2H), 2.37 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H);
13C NMR (75 MHz, CDCl3): d=178.9, 167.2, 154.2, 144.7,
139.1, 135.4, 134.9, 129.6, 129.4, 128.6, 126.9, 76.1, 65.8, 64.7,
61.3, 24.6, 24.4, 21.6, 14.2; IR: n=3348, 2975, 1698, 1606,
1468, 1399, 1321, 1247, 1168, 1094, 1048, 760, 701, 658,
572 cmÀ1; anal. calcd. for C23H25N3O5S2: C 56.66, H 5.17, N
8.62; found: C 56.39, H 5.34, N 8.68. Major diastereomer: ee
was determined by HPLC analysis (Chiralcel AD-H, i-
PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): retention
times tmajor =14.12 min, tminor =23.21 min, ee 99%.
4,4-Dimethyl-3-[(4S,5R)-2-thioxo-5-m-tolyl-1-tosylimida-
zolidine-4-carbonyl]oxazolidin-2-one (4j): White solid; [a]2D0:
1
À21 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): d=7.57–
7.54 (d, J=8.1 Hz, 2H), 7.37 (br, 1H), 7.23–7.12 (m, 5H),
7.09–7.06 (d, J=8.4 Hz, 2H), 6.21 (d, J=1.2 Hz, 1H), 4.89
(d, J=1.8 Hz, 1H), 4.14 (s, 2H), 2.36 (s, 3H), 2.28 (s, 3H),
1.62 (s, 3H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
179.0, 167.2, 154.2, 144.7, 138.9, 138.2, 134.9, 129.9, 129.5,
129.0, 128.6, 127.4, 124.2, 76.1, 66.0, 64.7, 61.4, 24.6, 24.4,
21.6, 21.4; IR: n=3346, 2981, 1694, 1610, 1454, 1386, 1248,
1153, 1095, 1037, 761, 698, 642, 571 cmÀ1; anal. calcd. for
C23H25N3O5S2: C 56.66, H 5.17, N 8.62; found: C 56.90, H
5.30, N, 8.71. Major diastereomer: ee was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane=30/70,
1.0 mLminÀ1, 245 nm): retention times
major =11.39 min, ee 96%.
tminor =9.32 min,
3-[(4S,5R)-5-(2-Fluorophenyl)-2-thioxo-1-tosylimidazoli-
dine-4-carbonyl]-4,4-dimethyloxazolidin-2-one (4g): Color-
t
4,4-Dimethyl-3-[(4S,5R)-2-thioxo-5-o-tolyl-1-tosylimidazo-
1
less needles; [a]2D0: +11 (c 1.0, CHCl3). H NMR (300 MHz,
lidine-4-carbonyl]oxazolidin-2-one (4k): White solid; [a]2D0:
1
CDCl3): d=7.58–7.55 (d, J=8.4 Hz, 2H), 7.36–7.31 (m, 2H),
7.23 (br, 1H), 7.15–7.12 (d, J=8.4 Hz, 2H), 7.05–6.99 (m,
2H), 6.19–6.18 (d, J=1.2 Hz, 1H), 4.88 (d, J=1.8 Hz, 1H),
4.14 (s, 2H), 2.37 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H);
13C NMR (75 MHz, CDCl3): d=179.0, 167.2, 154.2, 145.0,
134.8, 134.3, 129.4, 129.1, 128.9, 128.8, 116.1, 115.8, 76.1,
65.4, 64.6, 61.4, 24.7, 24.4, 21.6; IR: 3346, 3046, 2971, 1746,
À33 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): d=7.66–
7.63 (d, J=8.1 Hz, 2H), 7.22–7.20 (m, 4H), 7.17–7.14 (d, J=
8.1 Hz, 2H), 6.69–6.68 (d, J=1.8 Hz, 1H), 4.69 (d, J=
1.8 Hz, 1H), 4.12 (s, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.61 (s,
6H); 13C NMR (75 MHz, CDCl3): d=178.5, 167.0, 154.3,
144.9, 136.9, 134.9,131.0, 129.6, 128.9, 128.8, 127.0, 76.1, 64.7,
62.2, 61.4, 24.5, 24.4, 21.7, 19.3; IR: n=3426, 3191, 3058,
2979, 1746, 1478, 1369, 1266, 1175, 1090, 1066, 1024,
740 cmÀ1; anal. calcd. for C23H25N3O5S2: C 56.66, H 5.17, N
8.62; found: C 56.94, H 5.07, N 8.33. Major diastereomer: ee
was determined by HPLC analysis (Chiralcel AD-H, i-
1622, 15010, 1228, 1085, 840, 758, 724, 682, 579, 570 cmÀ1
;
anal. calcd. for C22H22FN3O5S2: C 53.75, H 4.51, N 8.55;
found: C 54.01, H 4.58, N 8.32. Major diastereomer: ee was
determined by HPLC analysis (Chiralcel AD-H, i-PrOH/
Adv. Synth. Catal. 2011, 353, 1787 – 1796
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1793

Xianxing Jiang et al.
FULL PAPERS
PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): retention
times tminor =7.83 min, tmajor =11.47 min, ee 97%.
(d, J=8.4 Hz, 1H), 7.71–7.73 (d, J=8.1 Hz, 1H), 7.27–7.53
(m, 6H), 6.19 (s, 1H), 4.33–4.56 (m, 2H), 2.37–2.41 (m,
5H); 13C NMR (75 MHz, DMSO-d6): d=179.1, 174.8, 171.6,
145.6, 142.3, 135.7, 135.4, 133.9, 129.7, 129.3, 129.3, 128.9,
126.1, 70.6, 64.9, 35.8, 21.5; IR: n=3289, 3060, 2920, 2853,
1364, 1491, 1338, 1157, 1090, 1014, 665, 542 cmÀ1; HR-MS
(ESI): m/z=437.0396, calcd. for C19H17ClN2O4S2 +H+:
437.0391; D=1.1 ppm. Major diastereomer: ee was deter-
mined by HPLC analysis (Chiralcel AD-H, i-PrOH/
hexane=30/70, 1.0 mLminÀ1, 245 nm): retention times:
3-[(4S,5S)-5-(Furan-2-yl)-2-thioxo-1-tosylimidazolidine-4-
carbonyl]-4,4-dimethyloxazolidin-2-one (4l): Colorless solid;
1
[a]2D0: +39 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3): d=
7.61–7.59 (d, J=8.1 Hz, 2H), 7.34 (br, 1H), 7.21–7.20 (m,
1H), 7.19–7.17 (d, J=8.1 Hz, 2H), 6.62–6.61 (d, J=3.3 Hz,
1H), 6.43–6.41 (m, 2H), 5.06 (d, J=2.1 Hz, 1H), 4.14 (s,
2H), 2.38 (s, 3H), 1.62 (s, 3H), 1.61 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=178.2, 166.6, 154.2, 149.8, 144.8, 143.4,
134.8, 129.3, 128.9, 110.8, 110.7, 76.1, 61.6, 61.4, 58.9, 24.6,
24.5, 21.7. IR: n=3412, 1781, 1698, 1478, 1392, 1365, 1266,
1230, 1171, 1092, 748 cmÀ1; anal. calcd. for C20H21N3O6S2: C
51.82, H 4.57, N 9.07; found: C 52.03, H 4.48, N 9.33. Major
diastereomer: ee was determined by HPLC analysis (Chiral-
cel AD-H, i-PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm):
retention times tminor =12.12 min, tmajor =22.57 min, ee 98%.
tminor =10.71 min, tmajor =13.16 min, ee 93%.
AHCTUNGTRENNUNG
[4.4]nonan-6-one (4p): White solid; [a]2D0: À11 (c 1.0,
CHCl3). 1H NMR (300 MHz, DMSO-d6): d=7.79–7.81 (d,
J=8.1 Hz, 1H), 7.70–7.73 (d, J=8.1 Hz, 1H), 7.14–7.39 (m,
6H), 6.09 (s, 1H), 4.39–4.56 (m, 2H), 3.38 (s, 3H), 2.26–2.40
(m, 5H); 13C NMR (75 MHz, DMSO-d6): d=179.3, 171.5,
145.4, 142.9, 137.9, 135.5, 129.7, 129.5, 128.5, 127.1, 126.8,
126.1, 71.5, 68.1, 64.8, 63.3, 36.1, 21.5; IR: n=3321, 3064,
2924, 2855, 1777, 1491, 1351, 1209, 1160, 1021, 664, 541 cmÀ1
;
General Procedure for the Organocatalytic
Asymmetric Synthesis of Spirocyclic Thioureas via
Mannich Reaction of Isothiocyanate (1c) with N-
Tosylimines
HR-MS (ESI): m/z=417.0942, calcd. for C20H20N2O4S2 +H+:
417.0937; D=1.2 ppm. Major diastereomer: ee was deter-
mined by HPLC analysis (Chiralcel AD-H, i-PrOH/
hexane=30/70, 1.0 mLminÀ1, 245 nm): retention times
To a stirred solution of 3g (0.006 mmol, 3.0 mol%) and N-
tosylimine (0.30 mmol) in dry toluene (1.5 mL), isothiocya-
nate 1c (0.20 mmol) was added under argon, The solution
was stirred at À158C for 6 h. After the reaction was com-
pleted (monitored by TLC), the resulting mixture was con-
centrated under reduced pressure and the residue was puri-
fied through column chromatography on silica gel to give
the optical pure spirocyclic products.
t
minor =5.47 min, tmajor =12.21 min, ee 96%.
AHCTUNGTRENNUNG
[4.4]nonan-6-one (4q): White solid; [a]2D0: À15 (c 1.0,
CHCl3). 1H NMR (300 MHz, DMSO-d6): d=7.80–7.83 (d,
J=8.4 Hz, 1H), 7.38–7.40 (d, J=8.1 Hz, 1H), 7.17–7.32 (m,
6H), 6.09 (s, 1H), 4.48–4.50 (m, 2H), 3.35 (s, 3H), 2.31–2.41
(m, 5H); 13C NMR (75 MHz, DMSO-d6): d=171.1, 144.9,
142.5, 138.1, 135.1, 133.1, 129.1, 128.9, 127.9, 126.6, 70.9,
67.6, 64.2, 62.8, 35.5, 21.1; IR: n=3320, 3058, 2912, 2853,
1690, 1511, 1491, 1356, 1204, 1160, 1021, 661, 541 cmÀ1; HR-
MS (ESI): m/z= 417.0932, calcd. for C20H20N2O4S2 +H+:
417.0937; D=1.2 ppm.
ACHTUNGTRENNUNG(4R,5S)-4-Phenyl-2-thioxo-3-tosyl-7-oxa-1,3-diazaspiro
[4.4]nonan-6-one (4m): White solid; [a]2D0: À17 (c 1.0,
1
CHCl3). H NMR (300 MHz, DMSO-d6): d=10.12 (br, 1H),
7.81–7.84 (d, J=7.8 Hz, 1H), 7.61–7.64 (d, J=8.1 Hz, 1H),
7.29–7.41 (m, 7H), 6.16 (s, 1H), 4.18–4.54 (m, 2H), 2.38–
2.41 (m, 5H); 13C NMR (75 MHz, DMSO-d6): d=178.7,
174.4, 171.0, 144.9, 136.2, 135.2, 129.1, 128.9, 128.8, 128.4,
126.6, 70.9, 68.0, 65.4, 64.3, 35.5, 28.9, 21.1; IR: n=3337,
2921, 2853, 2527, 1777, 1473, 1365, 1165, 1084, 1018, 667,
General Procedure for Synthesis of Biologically
Active Chiral Methylthioimidazolines
583 cmÀ1
;
HR-MS (ESI): m/z=403.0778, calcd. for
To a stirred solution of 3g (0.006 mmol, 3.0 mol%) and N-
tosylimine (0.30 mmol) in dry toluene (1.5 mL), isothiocya-
nate 1a (0.20 mmol) was added under argon, The solution
was stirred at À158C for 18 h. After the reaction was com-
pleted (monitored by TLC), the resulting mixture was con-
centrated under reduced pressure and the residue was puri-
fied through column chromatography on silica gel to give
the optical pure pruducts. To a mixture of the cyclic thiour-
eas and anhydrous K2CO3 (1.20 equiv.) in 2.5 mL acetone
was added MeI (1.10 equiv.) dropwise at 08C. Then the reac-
tion was stirred for 8 h. and concentrated under vacuum.
The mixture was applied to chromatography to afford the
purified methylthioimidazoline products. The enantiomeric
purity of the product was determined by using HPLC.
C19H18N2O4S2 +H+: 403.0781; D=0.7 ppm. Major diastereo-
mer: ee was determined by HPLC analysis (Chiralcel AD-
H, i-PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): retention
times tminor =12.05 min, tmajor =19.12 min, ee 90%.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1.0, CHCl3). 1H NMR (300 MHz, DMSO-d6): d=7.96–7.99
(d, J=7.8 Hz, 1H), 7.70–7.73 (d, J=8.1 Hz, 1H), 7.20–7.71
(m, 6H), 6.08 (s, 1H), 4.11–4.50 (m, 2H), 1.85–2.42 (m,
5H); 13C NMR (75 MHz, DMSO-d6): d=178.6, 174.7, 145.4,
144.9, 135.4, 135.3, 134.1, 132.0, 129.7, 129.5, 129.3, 129.2,
128.8, 116.5, 67.9, 67.4, 66.3, 65.9, 64.9, 35.8, 29.7, 21.5. IR:
n=3416, 3366, 2922, 2846, 1776, 1455, 1357, 1163, 1069,
1019, 666, 586 cmÀ1; HR-MS (ESI): m/z=421.0685, calcd.
for C19H17FN2O4S2 +H+: 421.0687; D=0.5 ppm. Major dia-
stereomer: ee was determined by HPLC analysis (Chiralcel
AD-H, i-PrOH/hexane=30/70, 1.0 mLminÀ1, 245 nm): re-
tention times tminor =4.99 min, tmajor =11.64 min, ee 95%.
4,4-Dimethyl-3-[(4S,5R)-2-(methylthio)-5-phenyl-1-tosyl-
4,5-dihydro-1H-imidazole-4-carbonyl]oxazolidin-2-one
(TID-1): Colorless solid; [a]2D0: À17 (c 1.0, CHCl3). H NMR
1
(300 MHz, CDCl3): d=7.69–7.67 (d, J=8.4 Hz, 2H), 7.29–
7.23 (m, 5H), 7.22–7.19 (d, J=8.4 Hz, 2H), 5.64–5.62 (d, J=
4.2 Hz, 1H), 5.56–5.55 (d, J=4.2 Hz, 1H), 3.99 (s, 2H), 2.50
(s, 3H), 2.39 (s, 3H), 1.47 (s, 3H, 1.36 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=169.7, 160.6, 153.2, 144.4, 139.8, 135.4,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1794
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1787 – 1796

Enantioselective Synthesis of Cyclic Thioureas via Mannich Reaction
129.4, 128.7, 128.3, 128.0, 126.9, 75.8, 75.3, 66.7, 60.6, 24.8,
24.0, 21.6, 15.5; IR: n=3394, 2972, 2930, 2256, 1779, 1706,
1571, 1363, 1306, 1162, 1093, 672 cmÀ1; HR-MS (ESI): m/z=
488.1305, calcd. for C23H25N3O5S2 +H+: 488.1308; D=
0.6 ppm. Major diastereomer: ee was determined by HPLC
5.62–5.60 (d, J=4.5 Hz, 1H), 5.56–5.55 (d, J=4.2 Hz, 1H),
4.00 (s, 2H), 2.52 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H),1.49 (s,
3H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3): d=169.6,
160.3, 153.2, 144.3, 139.4, 138.4, 135.5, 129.7, 129.3, 129.2,
128.6, 128.0, 127.4, 126.5, 124.2, 75.7, 75.3, 66.7, 60.7, 24.7,
24.0, 21.6, 21.3, 15.6; IR: n=3384, 2971, 2928, 2252, 1779,
1706, 1570, 1362, 1306, 1165, 1092, 672 cmÀ1; HR-MS (ESI):
m/z=502.1470, calcd. for C24H27N3O5S2 +H+: 502.1465; D=
1.0 ppm. Major diastereomer: ee was determined by HPLC
analysis
1.0 mLminÀ1, 245 nm): retention times
major =19.27 min, ee 97%.
3-[(4S,5R)-5-(2-Fluorophenyl)-2-(methylthio)-1-tosyl-4,5-
(Chiralcel
AD-H,
i-PrOH/hexane=30/70,
t
minor =13.74 min,
t
analysis
1.0 mLminÀ1, 245 nm): retention times
major =13.25 min, ee 99%.
(Chiralcel
AD-H,
i-PrOH/hexane=30/70,
dihydro-1H-imidazole-4-carbonyl]-4,4-dimethyloxazolidin-2-
one (TID-2): Colorless needles; [a]2D0: À50 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d=7.83–7.80 (d, J=8.4 Hz,
2H), 7.40–7.30 (m, 4H), 7.16–7.11 (m, 1H), 7.03–6.97 (m,
1H), 5.75–5.74 (d, J=4.5 Hz, 1H), 5.69–5.67 (d, J=4.5 Hz,
1H), 3.99 (s, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 1.45 (s, 3H,
1.35 (s, 3H); 13C NMR (75 MHz, CDCl3): d=169.6, 160.6,
158.0, 153.2, 144.7, 134.6, 129.9, 129.8, 129.6, 128.1, 127.6,
127.4, 124.6, 124.6, 115.6, 115.3, 75.3, 74.8, 60.9, 60.6, 24.6,
24.0, 21.6, 15.5; IR: n=3396, 2972, 2931, 2957, 1779, 1708,
1574, 1366, 1306, 1176, 1093, 671 cmÀ1; HR-MS (ESI): m/z=
506.1209, calcd. for C23H24FN3O5S2 +H+: 506.1214; D=
1.0 ppm. Major diastereomer: ee was determined by HPLC
t
minor =12.41 min,
t
Acknowledgements
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (Nos. 20932003 and 90813012), the
Key National S&T Program “Major New Drug Develop-
ment” of the Ministry of Science and Technology of China
(2009ZX09503-017), the Fundamental Research Funds for
the Central Universities of China (860618).
analysis
1.0 mLminÀ1, 245 nm): retention times
major =12.56 min, ee 95%.
3-[(4S,5R)-5-(2-Chlorophenyl)-2-(methylthio)-1-tosyl-4,5-
(Chiralcel
AD-H,
i-PrOH/hexane=30/70,
tminor =9.89 min,
t
References
dihydro-1H-imidazole-4-carbonyl]-4,4-dimethyloxazolidin-2-
one (TID-3): Colorless needles; [a]2D0: À90 (c 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): d=7.91–7.89 (d, J=8.4 Hz,
2H), 7.46–7.27 (m, 4H), 7.26–7.23 (m, 2H), 5.93–5.92 (d, J=
3.9 Hz, 1H), 5.66–5.64 (d, J=3.9 Hz, 1H), 3.98 (s, 2H), 2.48
(s, 3H), 2.44 (s, 3H), 1.46 (s, 3H, 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3): d=169.5, 160.6, 153.1, 144.8, 134.6, 131.5,
129.6, 129.6, 129.3, 128.3, 127.5, 75.2, 65.8, 63.8, 60.6, 24.6,
24.1, 21.6, 15.5; IR: n=3398, 2971, 2932, 2256, 1779, 1707,
1574, 1365, 1305, 1163, 1092, 670 cmÀ1; HR-MS (ESI): m/z=
522.0929, calcd. for C23H24ClN3O5S2 +H+: 522.0919; D=
1.9 ppm. Major diastereomer: ee was determined by HPLC
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analysis
1.0 mLminÀ1, 245 nm): retention times
major =14.39 min, ee 97%.
4,4-Dimethyl-3-[(4S,5R)-2-(methylthio)-5-o-tolyl-1-tosyl-
(Chiralcel
AD-H,
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t
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t
4,5-dihydro-1H-imidazole-4-carbonyl]oxazolidin-2-one
1
(TID-4): Colorless solid; [a]2D0: À23 (c 1.0, CHCl3). H NMR
(300 MHz, CDCl3): d=7.69–7.66 (d, J=8.1 Hz, 2H), 7.23–
7.20 (d, J=8.4 Hz, 2H), 7.16–7.09 (m, 4H), 5.95–5.94 (d, J=
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13C NMR (75 MHz, CDCl3): d=169.7, 160.2, 153.1, 144.4,
138.1, 135.4, 134.8, 130.6, 129.4, 128.0, 128.0, 126.7, 75.9,
75.3, 65.9, 60.6, 24.8, 23.8, 21.6, 19.3, 15.5; IR: n=3393,
2968, 2929, 2256, 1780, 1706, 1571, 1365, 1305, 1166, 1092,
673 cmÀ1
;
HR-MS (ESI): m/z=502.1461, calcd. for
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Adv. Synth. Catal. 2011, 353, 1787 – 1796
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Adv. Synth. Catal. 2011, 353, 1787 – 1796