Asymmetric aza-Mannich addition: Synthesis of modified chiral 2-(ethylthio)-thiazolone derivatives with anticancer potency

Article abstract of DOI:10.1021/ol200185h

An easily prepared cinchona alkaloid derivative was found to be an effective organocatalyst in a direct, enantioselective aza-Mannich addition. By establishing a quaternary carbon stereocenter, a series of modified chiral 2-(ethylthio)-thiazolone derivati

Full text of DOI:10.1021/ol200185h

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1494–1497
Asymmetric Aza-Mannich Addition:
Synthesis of Modified Chiral 2-(Ethylthio)-
thiazolone Derivatives with Anticancer
Potency
Xiaodong Liu,† Leijiao Deng,† Hongjin Song,† Huazhen Jia,† and Rui Wang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and
Molecular Biology, Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, Lanzhou University, Lanzhou 730000, China, and State Key Laboratory for
Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, China
wangrui@lzu.edu.cn
Received January 20, 2011
ABSTRACT
An easily prepared cinchona alkaloid derivative was found to be an effective organocatalyst in a direct, enantioselective aza-Mannich addition.
By establishing a quaternary carbon stereocenter, a series of modified chiral 2-(ethylthio)-thiazolone derivatives have been obtained with excellent
diastereo- and enantioselectivities. And these derivatives have been found to show anticancer activities against five different cancer cell lines
using the MTT assay.
One of the fundamental objectives of organic and med-
icinal chemistry has been the design, synthesis, and pro-
duction of molecules having value as human therapeutic
agents. In the past 10 years, the number of chiral, non-
racemic pharmaceuticals on the market was consistently
increasing. Many new single enantiomer drugs with a well-
timed chiral switch were produced to offer enhanced therapy,
more predictable pharmacokinetics, and reduced toxicity.1
It is becoming more and more important to prepare these
compounds using new enantioselective technologies to
minimize the losses incurred from making racemic mix-
tures. And organocatalysis has emerged to be an effective
way. Due to its operational and economic advantages, the
asymmetric organocatalysis has had a significant impact
in chemical synthesis and has developed into a practical
synthetic paradigm associated with the pharmaceutical
industry.2
With proven utility in biological chemistry, heterocyclic
compounds have received special attention gradually.3
There are numerous biologically active molecules with
(2) For some selected general reviews on asymmetric organocatalysis,
see: (a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew.
Chem., Int. Ed. 2008, 47, 6138. (b) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 4638. (c) Denmark, S. E.; Beutner, G. L. Angew.
Chem., Int. Ed. 2008, 47, 1560. (d) Dondoni, A.; Massi, A. Angew.
Chem., Int. Ed. 2008, 47, 463. (e) Xu, X.; Wang, W. Org. Biomol. Chem.
2008, 6, 2037. (f) List, B.; Yang, J. W. Science 2006, 313, 1584. (g) List, B.
Chem. Commun. 2006, 819. (h) Dalko, P. I.; Moisan, L. Angew. Chem.,
Int. Ed. 2004, 43, 5138. For the chiral drugs synthesis, see: Horton, D. A.;
Bourne, G. T.; Smyth, M. L. Chem. Rev. 2003, 103, 893.
(3) (a) Jin, Z. Nat. Prod. Rep. 2003, 20, 584. (b) Frazen, R. G.
J. Comb. Chem. 2000, 2, 195. (c) Lewis, J. R. Nat. Prod. Rep. 1999, 16,
389. (d) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97,
449. (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
(f) Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed. 1996, 35, 17.
† Lanzhou University.
‡ Lanzhou Institute of Chemical Physics.
(1) (a) The United States Adopted Names (USAN) Council in The
American Medical Association (AMA) (2005) Geometric Isomerism and
Chirality: The USAN Perspective. (b) Moran, P. New Ligands for Asym-
metric Hydrogenation, Specialty Chems. Magazine, July-Aug. 2003, 16.
r
10.1021/ol200185h
Published on Web 02/23/2011
2011 American Chemical Society

five-membered rings, containing two heteroatoms. And
the thiazole ring is the most widely existing one. According
to the literature, the thiazole ring is an important scaffold
associated with several biological active compounds.4 For
instance, several natural molecules with a thiazolidinone
moiety are known to possess significant antitumor, immuno-
suppressive, and antibiotic properties.5 In addition, the amino-
thiazole ring system has found application in the drug
development for the treatment of allergies, hypertension,
and HIV infections.6 However, to the best of our knowl-
edge, the research on modified thiazolone derivatives has
mainly focused on racemic ones. Only one example using
2-benzyloxythiazol-5(4H)-ones as substrates in asym-
metric addition was reported by Ooi’s group in 2010.7
Therefore, the development of new highly efficient organic
synthetic methods to access optically active thiazolone deriv-
atives would be of great value for the drug-lead synthesis.
According to Lin’s report,8 in addition to the main keto
form, 2,4-disubstituted thiazolones can also exist in other
tautomeric forms in the solvent (mainly having an enol
form and a conjugated keto form). When the electron-
donating group was introduced into the C-2 position, less
likely tautomerism was observed. Thus in order to elim-
inate the undesired reactions, we chose the 2-(ethylthio)-
thiazolones which have an ethylthio- group at the C-2
position as the nucleophile to explore this aza-Mannich
reaction in the nonpolar solvents.
Figure 1. Chiral cinchona alkaloid derived catalysts screened in
this work.
N-tosyl aldimines,9 and it was proven that the cinchona
alkaloid derivatives were highly efficient catalysts in the
chiral R-disubstituted R,β-diamino acid synthesis. On the
basis of this, we decided to investigate the cinchona
alkaloid catalyst system in this reaction to see whether it
is viable for the synthesis of masked chiral 2-(ethylthio)-
thiazolone derivatives.
At the outset of the study, a variety of chiral cinchona
alkaloid catalysts (Figure 1) were tested in the selected
reaction of substrates 1a and 2a in the ethyl ether at 30 °C.
Initially, as is shown in Table 1, at 20 mmol %, all of
quinine derived catalysts 1a-d could catalyze this model
reaction well except 1c (entry 4), and catalyst 1b was the
most effective one affording the product 4a with a high
diastereomeric ratio of 95:5 and good enantioselectivity
(entry 2). Replacing the -OTMS group at the R position
with the sterically bulky groups (-OTBDMS and -OSi-
(Ph)3) resulted in longer reaction times and an obvious
decrease of enantioselectivities. Subsequently, we investi-
gated the other cinchona alkaloid catalysts 1g-i derived
from the quinidine and cinchonine, and none of them
could perform better than the catalyst 1b as well.
Furthermore, in the previous communication we have
described the asymmetric addition of oxazolones with
(4) (a) Zhao, H. Drug Discovery Today 2007, 12, 149. (b) Biron, E.;
Chatterjee, J.; Kessler, H. Org. Lett. 2006, 8, 2417. (c) Deng, S.;
Taunton, J. Org. Lett. 2005, 7, 299. (d) Sperry, J. B.; Wright, D. L.
Curr. Opin. Drug Discovery Dev. 2005, 8, 723. (e) Allen, S.; Newhouse,
B.; Anderson, A. S.; Fauber, B.; Allen, A.; Chantry, D.; Eberhardt, C.;
Odingo, J.; Burgess, L. E. Bioorg. Med. Chem. Lett. 2004, 14, 1619.
€
(f) Bohm, H.-J.; Flohr, A.; Stahl, M. Drug Discovery Today: Technol.
2004, 1, 217. (g) Wermuth, C. G. In The Practice of Medicinal Chemistry,
2nd ed.; Academic Press: London, 2003; p 193. (h) Barreca, M. L.;
€
Balzarini, J.; Chimirri, A.; Clercq, E. D.; Luca, L. D.; Holtje, H. D.;
Holtje, M.; Monforte, A. M.; Monforte, P.; Pannecouque, C.; Rao, A.;
In addition, when the bifunctional thiourea-tertiary
amine 1j was used in this model reaction (entry 9), only a
racemic product was obtained. It suggested that the thiourea
functionality was disadvantageous in this reaction because
of its strongly basic effect. To further improve the enan-
tioselectivity, we conducted a cursory examination of the
influence of the reaction temperature. Interestingly, except
for a slightly prolonged reaction time, a higher ee value of
€
ꢀ
Zappala, M. J. Med. Chem. 2002, 45, 5410.
(5) (a) Siddiqui, I. R.; Singh, P. K.; Singh, J.; Singh, J. J. Agric. Food
Chem. 2003, 51, 7062. (b) Kenderekar, P. S.; Siddiqui, R. F.; Patil, P. S.;
Bhusare, S. R.; Pawar, R. P. Ind. J. Pharm. Sci. 2003, 65, 313. (c) Galietta,
J. V.; Verkman, A. S. J. Biol. Chem. 2002, 277, 29224. (d) Rzasa, R. M.;
Shea, H. A.; Romo, D. J. Am. Chem. Soc. 1998, 120, 591. (e) Mulzer, J.;
Mantoulider, A.; Ohler, E. Tetrahedron Lett. 1997, 38, 7725. (f) Badorc, A.;
Bordes, M. F.; DeCointel, P.; Savi, P.; Lale, A.; Petitou, M.; Maffrand,
J. P.; Herbert, J. M. J. Med. Chem. 1997, 40, 3393.
(6) (a) Reddy, K. H.; Reddy, P. S.; Babu, P. R. J. Inorg. Biochem. 1999,
77, 169. (b) Perez, J. M.; Matesanz, A. I.; Marin-Ambite, A.; Navarro, P.;
Alonso, C.; Souza, P. J. Inorg. Biochem. 1999, 75, 255. (c) Hall, I. H.; Cheen,
S. Y.; Barnes, B. J.; Wext, X. D. Met. Based Drugs 1999, 6, 143–147.
(7) (a) Uraguchi, D.; Koshimoto, K.; Ooi, T. Chem. Commun. 2010,
46, 300. For racemic ones, see:(b) Havrylyuk, D.; Zimenkovsky, B.;
Vasylenko, O.; Zaprutko, L.; Gzella, A.; Lesyk, R. Eur. J. Med. Chem.
2009, 4, 1396. (c) Khan, S. A.; Yusuf, M. Eur. J. Med. Chem. 2009, 44,
2597. (d) Verma, A.; Saraf, S. K. Eur. J. Med. Chem. 2008, 43, 897.
(e) Qiao, Q.; Dominique, R.; Goodnow, R., Jr. Tetrahedron Lett. 2008,
49, 3682. (f) Thompson, M. J.; Heal, W.; Chen, B. Tetrahedron Lett.
2006, 47, 2361. (g) Boy, K. M.; Guernon, J. M. Tetrahedron Lett. 2005,
46, 2251. (h) Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.;
Chen, D.-W. J. Org. Chem. 2003, 68, 7887. (i) Suzuki, M.; Morita, K.;
Yukioka, H.; Miki, N.; Mizutani, A. J. Pesticide Sci. 2003, 28, 37.
(j) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 1363.
(k) Marcantonio, K. M.; Frey, F. L.; Murry, J. A.; Chen, C.-Y.
Tetrahedron Lett. 2002, 43, 8845. (l) Qiao, Q.; So, S.-S.; Goodnow,
R. A., Jr. Org. Lett. 2001, 3, 3655.
(9) For reviews on chiral cinchona alkaloid catalysts, see: (a) Connon,
S. J. Chem. Commun. 2008, 2499. (b) Marcelli, T.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 7496. (c) Tian, S.-K.; Chen,
Y. G.; Hang, J. F.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621. (d) Chen, Y. G.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103, 2965.
For selected examples of chiral cinchona alkaloid catalysis, see:(e) Liu, Y.;
Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L. J. Am. Chem. Soc. 2009,
131, 41. (f) Dodda, R.; Goldman, J. J.; Mandal, T.; Zhao, C.-G.; Broker,
G. A.; Tiekink, E. R. T. Adv. Synth. Catal. 2008, 350, 537. (g) Liu, T.-Y.;
Cui, H.-L.; Chai, Q.; Long, J.; Li, B. J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C.
Chem. Commun. 2007, 2228. (h) Comer, E.; Rohan, E.; Deng, L., Jr.; Porco,
J. A. Org. Lett. 2007, 9, 2123. (i) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.;
Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (j) Saaby, S.;
Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (k) Yoon,
T. P.; Jacobsen, E. N. Science 2003, 299, 1691. For chiral cinchona alkaloid
catalysis in our group recently, see:(l) Sun, W. S.; Hong, L.; Liu, C. X.;
Wang, R. Org. Lett. 2010, 12, 3914. (m)Liu, X. D.;Deng, L. J.;Jiang, X. X.;
Yan, W. J.; Liu, C. L.; Wang, R. Org. Lett. 2010, 12, 876.
(8) Lin, Y. H.; Andersen, K. K. Eur. J. Org. Chem. 2002, 557.
Org. Lett., Vol. 13, No. 6, 2011
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Table 1. Representative Screening for the Addition of
2-(Ethylthio)-thiazolone 2a to N-Tosyl Imine 3aa
Table 2. Aza-Mannich Addtion of 2-(Ethylthio)-thiazolones
and N-Tosyl Aldiminesa
cat.
temp
time
(h)
yield
[%]b
ee
entry
(20 mmol %)
(°C)
drb
eec
entry
2, R1
3, R2
3a, Ph
drc
[%]d
1
1a
1b
1b
1c
1d
1e
1f
35
35
35
35
35
35
35
35
35
35
35
20
0
8
16
16
16
16
24
32
8
92:8
95:5
95:5
90:10
96:4
95:5
95:5
82:18
90:10
80:20
78:22
95:5
91:9
nd
57
86
85
13
81
77
60
35
67
17
0
1
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2a, iPr
2b, iBu
4a, 79
4b, 86
4c, 87
4d, 67
4e, 73
4f, 88
4g, 80
4h, 78
4i, 83
4j, 85f
4k, 78
4l, 94
4m, 90f
95:5
90
2
2
3b, o-F-Ph
>98:2
>98:2
>98:2
95:5
86
3d
4
3
3c, o-Cl-Ph
3d, m-Cl-Ph
3e, p-Cl-Ph
3f, o-Me-Ph
3g, m-Me-Ph
3h, o-Br-Ph
3i, p-CN-Ph
3j, 3,4-(Me)2-Ph
3k, 2-naphthyl
3l, 2-furyl
98
4
80
5
5
>99
>99
82
>99g
>99
90
6e
7e
8
90:10
92:8
6
7e
8
1g
1h
1i
>98:2
>98:2
83:17
91:9
9
16
36
8
9
10e
11
12
13
10
11
12
13
14f
1j
92
1b
1b
1b
18
20
48
90
81
nd
>98:2
75:25
96
3a, Ph
90/85
-40
a Unless indicated otherwise, all reactions were performed with
0.20 mmol of 2, 0.10 mmol of 3, and 0.02 mmol of 1b in 1.0 mL of ethyl
ether for 16 h, and full conversion was observed in all cases. b Yield of the
major diastereoisomer isolated by silica-gel column chromatography.
c Determined by 1H NMR spectroscopic analysis. d Determined by chiral
HPLC on a Chiralcel column. e The reaction was carried out with
0.02 mmol of quinine as catalyst under 0 °C for 18 h. f The yield of both
diastereoisomers. g The absolute configuration of 4h was determined by
X-ray crystal-structure analysis. The absolute configurations of the
other products were assigned by analogy.
a Unless indicated otherwise, all reactions were performed with
0.20 mmol of 2a, 0.10 mmol of 3a, and 20 mmol % of catalyst in 1.0 mL
of ethyl ether for 8-36 h, and full conversion was observed in all cases.
b Determined by 1H NMR measurements after purification. c Deter-
mined by chiral HPLC on a Chiralpak AD column. d 0.40 mmol of 2a
was used. e The conversion rate of the reactant was under 80% after 32 h.
f The conversion rate of the reactant was under 30% after 48 h. nd: not
determined.
90% with a maintained diastereomeric ratio was gained when
the reaction temperature was lowered to 20 °C (entry 12).
However, both the ee value and diastereomeric ratio have
shown an obvious decrease when the reaction temperature
was further cooled down to 0 °C. And under -40 °C, the
conversion rate of the reactant was still under 30% after
2 days of reaction.
With the optimized conditions established, the scope
of N-tosyl aldimines and 2-(ethylthio)-thiazolones in the
presence of 20 mmol % catalyst 1b was explored.
As is shown in Table 2, a majority of the reactions
proceeded smoothly to furnish the corresponding masked
chiral 2-(ethylthio)-thiazolone derivatives in moderate to
good yields and excellent diastereo- and enantioselectiv-
ities. For the reactions with the nucleophile 2-(ethylthio)-
thiazolone 2a, a wide rangeofsubstituentscould be present
at the aryl position on the N-tosyl imines. All of the aryl-
substituted substrates, whether electron-rich or electron-
deficient at different sites, seemed to have little influence
on the results of the diastereo- and enantioselectivity of the
reaction. A series of aza-Mannich adducts were obtained
in excellent diastereomeric ratios and ee values (entries 1-9).
The additions of more sterically hindered imines derived
from 3,4-dimethylbenzaldehyde and 2-naphthaldehyde
proceeded equally well with high enantioselectivities and
good diastereoselectivities. Outstanding diastereo- and
Figure 2. X-ray Structure of the adduct 4h.
enantioselectivity were also observed for the 2-(ethylthio)-
thiazolone with the 2-furanyl N-tosyl imine. In addition, a
high enantioselectivity with a moderate diastereomeric ratio
(75:25) was obtained when the 2-(ethylthio)-thiazolone
had an isobutyl substituent at the R2 position.10
(10) Under the optimized conditions, the alkyl-substituted isobutyl
N-tosyl imine showed no reactivity toward 2-(ethylthio)-thiazolone 2a.
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Org. Lett., Vol. 13, No. 6, 2011

dose-dependent inhibitory effect.12 A majority of them
showed inhibition on EJ, PC-3, HepG-2, and Jurkat with
an IC50 range of 20 to 30 μM (Table 3). And the analogues
4c and 4h having one ortho-halogen substituted phenyl
group showed significant inhibitory effects on the Jurkat
with IC50 values of 17 and 19 μM. Although 4c and 4h
exhibited weaker inhibitory activity (IC50 = 38 μM, 41 μM)
on the breast cancer cell MDA-MB-231, they were still the
most effective ones. Moreover, the different cytotoxicities
suggested that the cancer cell lines displayed different sensitiv-
ities to chiral masked 2-(ethylthio)-thiazolone derivatives.
In conclusion, it has been uncovered that, in the aza-
Mannich addition of 2-(ethylthio)-thiazolones and N-tosyl
aldimines, the cinchona alkaloid catalyst system could
perform efficiently. By establishing a carbon- and nitro-
gen-substituted quaternary carbon stereocenter, a series of
masked chiral 2-(ethylthio)-thiazolone derivatives have
been synthesized with high levels of diastereo- (up to
>98:2) and enantioselectivities (up to >99%) for the first
time. Several new derivatives have been found to show
potential anticancer activities. This preliminary study pro-
vided a foundation for the further development of new
single enantiomer anticancer drugs.
Table 3. IC50 Values of Masked Chiral 2-(Ethylthio)-thiazolone
Derivatives on the Growth of Human Cancer Cell Linesa
Compound
4a
4b
4c
4f
4h
4i
4l
EJ
25
29
49
26
29
32
34
57
23
27
20
23
38
20
17
28
30
59
24
29
22
27
41
22
19
26
25
47
25
28
30
33
68
24
28
PC-3
MDA-MB-231
HepG-2
Jurkat
a Values are means of three experiments each done in duplicate. IC50
values are expressed in μM. EJ, PC-3, MDA, HepG-2, and Jurkat cells
were seeded at a density of 5000 cells in 96-well plates. Compounds
were added 24 h after seeding. After 2 days in culture, the MTT stock
solution (5 mg/mL in PBS) was added to each well and incubated at
37 °C for 4 h. The medium was removed carefully, and dimethyl sulfoxide
was added to each well to dissolve formazan. The absorbance of
each well at 490 nm was measured by using a Bio-Rad Model 680
microplate reader.
The constitution and absolute configuration of the product
4h were determined by X-ray crystallography (Figure 2) as
well as by NMR spectroscopic studies.11
Inviewof the casein which wewereabletoaccessdiverse
enantiopure masked 2-(ethylthio)-thiazolone derivatives,
wedecidedtoevaluate the biological activitiesof them. The
compounds 4a, 4b, 4c, 4f, 4h, 4i, and 4l were prepared to
test for their cytotoxic activity on five human cancer cell
lines using the MTT assay. A summary of the IC50 values is
shown in Table 3. To all of the cancer cell lines we tested,
masked 2-(ethylthio)-thiazolone derivatives presented a
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (90813012 and 20932003) and
National S&T Major Project of China (2009ZX09503-017).
Supporting Information Available. Experimental details,
characterization data for the products, and crystal structure
data of the adduct 4h in CIF format. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(11) CCDC 800993 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
daa_request/cif.
(12) The dose-dependent growth inhibition ability was shown in the
Supporting Information.
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