Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via CS2 mediated decarboxylation cyclization

Article abstract of DOI:10.1016/j.tetlet.2020.151847

A mild and cost-effective decarboxylation cyclization method was developed for the synthesis of chiral 5-substituted thiazolidine-2-thione derivatives from β-amino oxazolidinones. This reaction was mediated by CS₂ and allowed a highly stereoselective synthesis of linezolid thiazolidine-2-thione derivatives. The chirality of the linezolid base was completely retained in the final product.

Full text of DOI:10.1016/j.tetlet.2020.151847

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
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Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via
CS2 mediated decarboxylation cyclization
De-Yun Cui a,b,#, Hong-Tao Kong a,#, Yi Yang a, Jianfeng Cai c, Bo-Yuan Shen a, Da-chao Yan a,
Xiu-Juan Zhang a, Ying-Long Qu a, Meng-Meng Bai a, En Zhang a,c,
⇑
a School of Pharmaceutical Sciences, Institute of Drug Discovery and Development, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China,
Zhengzhou University, Zhengzhou 450001, China
b West China School of Pharmacy, Sichuan University, Sichuan 610041, China
c Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and cost-effective decarboxylation cyclization method was developed for the synthesis of chiral 5-
substituted thiazolidine-2-thione derivatives from b-amino oxazolidinones. This reaction was mediated
by CS2 and allowed a highly stereoselective synthesis of linezolid thiazolidine-2-thione derivatives.
The chirality of the linezolid base was completely retained in the final product.
Ó 2020 Published by Elsevier Ltd.
Received 18 February 2020
Revised 12 March 2020
Accepted 13 March 2020
Available online xxxx
Keywords:
Asymmetric synthesis
Cyclization
Stereoselectivity
Chirality
Linezolid thiazolidine-2-thione
Introduction
To date, various methods have been reported for the synthesis
of thiazolidine-2-thiones. Commonly, thiazolidine-2-thione can
The thiazolidine-2-thione motif is a key substructure of various
organic compounds that have central roles in multiple domains
[1,2]. Thiazolidinethiones (Fig. 1, 1) are well known as powerful
chiral auxiliaries [3–5]. These efficiently complement the Evans’
chiral N-acyl oxazolidinones [6] with high stereoselective control
for specific substrates, including acetate [7]. Thiazolidinethione
chiral auxiliaries can be transformed into various functional groups
[8]. These chiral auxiliaries have been successfully applied to the
synthesis of natural products [9,10] and antibiotic skeletons [11].
Compounds that contain thiazolidine-2-thione fragments have
a wide range of biological activities, such as regulation of apoptosis
in cancer chemotherapy (Fig. 1, BH3I-1Br), [12] antifungal activity
(Fig. 1, Fezatione) [1], Escherichia coli b-ketoacyl-(acyl-carrier-
protein) synthase III inhibition and antimalarial activity (Fig. 2, 2)
[13], and hepatoprotective effects [14]. Acyl-1,3-thiazolidine-2-
thione has also been used for selective etherification of the primary
alcohols of diols and polyols [15–17].
be synthesized by the reaction of carbon disulfide with b-amino
alcohols [18,19], b-amino thiols [20,21] or azridines [22,23]. Both
the electrogenerated-base method [24] and microwave-assisted
method [25] can improve the reaction yield and time. Multicompo-
nent reactions have also been used for the synthesis of thiazo-
lidine-2-thiones [26–28]. However, few studies have investigated
the synthesis and further applications of 5-substituted thiazo-
lidine-2-thiones [29,30]. Hence, there is still a need for the effective
synthesis of chiral 5-substituted thiazolidine-2-thiones.
Oxazolidinones are a novel class of orally active synthetic
antibacterial agents [31]. Linezolid is a representative oxazolidone
antibacterial drug that has excellent activity against almost all
Gram-positive pathogens [32,33]. However, reversible myelosup-
pression has been reported with high doses of linezolid [33]. To
improve the safety profile, various efforts have been made to mod-
ify linezolid. Besides tedizolid phosphate (Fig. 2), several other oxa-
zolidinone drug candidates are currently undergoing clinical phase
trials (Fig. 2, MRX-1 and Radezolid) [34]. Racemic thiazo-
lidinethione analogs of linezolid with good activity against fungi
have been prepared by transforming the oxazolidinone ring oxygen
into a bulkier sulfur atom [35]. The development of new and effi-
cient synthetic approaches towards chiral thiazolidine-2-thione
substructures will help medicinal chemists to modify linezolid.
⇑
Corresponding author at: School of Pharmaceutical Sciences, Institute of Drug
Discovery and Development, Key Laboratory of Advanced Pharmaceutical
Technology, Ministry of Education of China, Zhengzhou University, Zhengzhou
450001, China.
E-mail address: zhangen@zzu.edu.cn (E. Zhang).
De-Yun Cui and Hong-Tao Kong contributed equally.
#
https://doi.org/10.1016/j.tetlet.2020.151847
0040-4039/Ó 2020 Published by Elsevier Ltd.
Please cite this article as: D.-Y. Cui, H. T. Kong, Y. Yang et al., Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via CS2 mediated decar-
boxylation cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151847

2
D.-Y. Cui et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of the reaction conditionsa.
Entry
Base
Solvent
Yieldb 5a (%)
1
2
3
4
5
6
7
8
Na2CO3
DIPEA
Et3N
NaOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Acetone
DCE
65
71
57
69
53
74
58
90
25
14
Trace
80
28
Fig. 1. Representative compounds containing the thiazolidine-2-thione
substructure.
NaHCO3
Na3PO4Á12H2O
K2CO3
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
Na3PO4Á12H2O
None
9
10
11
12
13
14
15
16
17
EtOH
Toluene
DMSO
DCM
THF
DMF
67
35
Acetone
Acetone
93c
n.r.d
a
Reagents and conditions: 3a (150 mg, 0.38 mmol, 1 equiv.), CS2 (0.38 mmol, 1
Fig. 2. Structures of linezolid and other biologically active oxazolidinones.
equiv.), base (0.38 mmol, 1 equiv.), solvent (5 mL), r.t., 18 h.
b
Isolated yield based on 3a.
24 h.
c
d
Results and Discussion
n.r. = no reaction.
In our endeavor to identify more potent compounds with excel-
lent antimicrobial activity against drug-resistant bacteria [36–40],
dithiocarbamate derivatives [41,42] and picolinic acid derivatives
[43] were found to be good metallo-beta-lactamase inhibitors that
could improve meropenem antimicrobial activity up to 2569 times
against strains containing blaNDM-1 genes [41]. Inspired by the
extensive application of linezolid against major Gram-positive
pathogenic bacteria, including vancomycin-resistant Enterococcus
faecium, methicillin-resistant Staphylococcus aureus and peni-
cillin-resistant Streptococcus pneumonia [44], dithiocarbamate
derivatives based on the linezolid skeleton were designed as met-
allo-beta-lactamase inhibitors (Scheme 1). However, an unex-
pected product, thiazolidinethione 5a, was obtained in 65% yield
instead of oxazolidinone 4a when 3a was reacted under weakly
basic conditions (Scheme 1, entry 1 in Table 1).
Table 2
Substrate scope of thiazolidine-2-thione analogs of linezolid.a,b.
On the basis of this unexpected finding, the reaction conditions
were optimized using different bases and solvents to improve the
efficiency of the reaction (Table 1, Entries 1–7). The results showed
that NaOH and N,N-diisopropylethylamine (DIPEA) slightly
improved the yield compared with Et3N (Table 1, entries 2–4).
The use of Na3PO4Á12H2O as a base also gave a better yield (74%).
Screening a series of solvents showed that acetone performed bet-
ter than other solvents (Table 1, entries 8–15). Product 5a was
obtained in the lowest yield in EtOH and only traces were observed
in toluene. A small increase in the yield (Table 1, entry 16) was
obtained when the reaction time was increased to 24 h. No reac-
tion was observed in the absence of a base (Table 1, entry 17).
After optimization of the reaction conditions, the substrate
scope of the reaction was investigated (Table 2). First, substrates
3a–c with various alkyl substituents were screened. Although all
alkyl substrates reacted successfully, the yield decreased with
aReagents and conditions: 1 (0.38 mmol, 1 equiv.), CS2 (0.38 mmol, 1 equiv.),
Na3PO4Á12H2O (0.38 mmol, 1 equiv.), acetone (5 mL), r.t., 24 h. bIsolated yield based
on 1. cYield on a gram scale.
increasing length of the alkyl chain (5a–c). Unsaturated alkane
and cyclopropane substituents were suitable for this reaction and
gave the product in moderate yields (5u and 5v). Next, the effect
of aromatic benzyl substituents was examined. The reaction pro-
ceeded smoothly both for substrates bearing an electron-donating
group on the benzyl group (5d–g) and those with electron-with-
drawing mono- and disubstituted substituents on the benzyl
Scheme 1. Unexpected one-pot decarboxylation reaction.
Please cite this article as: D.-Y. Cui, H. T. Kong, Y. Yang et al., Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via CS2 mediated decar-
boxylation cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151847

D.-Y. Cui et al. / Tetrahedron Letters xxx (xxxx) xxx
3
group. In most cases, the products were obtained in >80% yield
(5h–n). Notably, with electron-withdrawing substituents such as
F and Cl, a higher yield was obtained when substitution was in
the para-position than in the ortho- or meta-position. Methylnaph-
thalene and various substituted naphthalene and heterocyclic aro-
matics such as picoline and thiophene were also viable for this
reaction and gave the corresponding products (5o–t). Different
esters, which were sensitive to base, were also suitable for this pro-
cess and gave moderate yields of the products (5w–x). Unfortu-
nately, primary amino or acetyl substrates did not react at all.
Substrates containing ether or cyano groups also failed in this reac-
tion. An experiment with reaction scale on the gram level indicated
that this had little influence on the yield (5d).
To confirm whether the stereochemistry of the product was lost
in this reaction and to explore the mechanism of the CS2-mediated
one-pot decarboxylation reaction, racemic 5d was prepared by the
same method as 5d. Compared with racemic 5d, HPLC using an
appropriate column showed the enantioselectivity of compound
5d was >99% enantiomeric excess. The absolute configuration of
thiazolidinethione 5d was established as (S) by X-ray crystallogra-
phy (Fig. S1) [45].
Based on the stereochemistry of 3a and 5a, a plausible reaction
mechanism for the CS2 mediated decarboxylation cyclization is
shown in Scheme 2. Oxazolidinone 3 reacts with CS2 under weakly
basic conditions to form dithiocarbamate 6. Oxazolidinone ring
opening of dithiocarbamate 6 gives intermediate 7 via nucleophilic
substitution (SN2). In this step, 6 undergoes configuration inver-
sion. Finally, 5 was obtained by the decarboxylation of 7 [46].
To our delight, selected compounds showed anticancer effects
on human esophageal cancer cells (EC109), human bladder cancer
cells (EJ) and human gastric cancer cell lines (MGC803) (Fig. 3).
Compound 5v exhibited the best cytotoxicity on EJ
Scheme 2. Proposed mechanism.
(a)
(IC50 = 61.607
1.790 lg/mL) and MGC803 (IC50 = 65.584
1.817 g/mL) (Fig. 4). In addition, the antibacterial activities of
l
thiazolidine-2-thione 5a-x against three Gram-positive bacteria
Staphylococcus aureus, Enterococcus faecalis, Bacillus Subtilis and
four Gram-negative Escherichia coli, Pseudomonas maltophilia,
(a)
(b)
(b)
(c)
Fig. 3. Cell inhibition rates for 72 h treatment at 64 lg/mL. (a) human esophageal
cancer cells (EC109). (b) human bladder cancer cells (EJ). (c) human gastric cancer
Fig. 4. Fit curve of IC50 (50% inhibitory concentration) of compound 5v. (a) human
cells (MGC803).
gastric cancer cell lines (MGC803). (b) human bladder cancer cells (EJ).
Please cite this article as: D.-Y. Cui, H. T. Kong, Y. Yang et al., Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via CS2 mediated decar-
boxylation cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151847

4
D.-Y. Cui et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 3
MICs of compounds and commercial antibiotics.
MIC (lg/mL)
Gram-positive bacteria
Com.
5a
5a
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
S.aa
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
1
E.fb
B.sc
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
E.cd
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
P.me
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
K.pf
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
Seg
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
5s
5t
5u
5v
5w
5x
Vh
Mi
j
j
j
j
j
j
—
—
—
0.0625
—
—
—
—
—
j
j
j
j
j
j
—
—
—
—
a
b
c
d
e
f
Staphylococcus aureus.
Enterococcus faecalis.
Bacillus subtilis.
Escherichia coli.
Pseudomonas maltophilia.
Klebsiella pneumonia.
Salmonella.
Vancomycin.
Meropenem.
g
h
i
j
Not determined.
Klebsiella pneumonia, Salmonella were evaluated. However, the
Appendix A. Supplementary data
minimum inhibitory concentration (MIC) of these compounds
were >64
lg/mL (Table 3).
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.151847.
Conclusion
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In summary, we have developed a new route toward the asym-
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high yields of chiral 5-substituted thiazolidine-2-thione products.
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Please cite this article as: D.-Y. Cui, H. T. Kong, Y. Yang et al., Asymmetric synthesis of linezolid thiazolidine-2-thione derivatives via CS2 mediated decar-
boxylation cyclization, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2020.151847