Exploration of the structure–activity relationship and druggability of novel oxazolidinone-based compounds as Gram-negative antibacterial agents

Article abstract of DOI:10.1002/ardp.201900129

To gain further knowledge of the structure–activity relationship and druggability of novel oxazolidinone-based UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) inhibitors as Gram-negative antibacterial agents, compounds containing the hydrophobic tails

Full text of DOI:10.1002/ardp.201900129

Received: 27 April 2019
Revised: 5 August 2019
Accepted: 8 August 2019
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DOI: 10.1002/ardp.201900129
F U L L P A P E R
Exploration of the structure–activity relationship and
druggability of novel oxazolidinone‐based compounds as
Gram‐negative antibacterial agents
Shi Ding1,2
Xing‐Long Zhu1
Ye Chen1
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Jing‐Chao Ji1
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Ming‐Juan Zhang1
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Yu‐She Yang2
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Rui Wang3
Ju Liu1
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Li‐Hong Wang1
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Yi Zhong1
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Le Gao1 Man Lu1
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1Key Laboratory of New Drug Research and
Development of Liaoning Province, College of
Pharmacy, Liaoning University, Shenyang,
Liaoning, China
Abstract
To gain further knowledge of the structure–activity relationship and druggability
of novel oxazolidinone‐based UDP‐3‐O‐acyl‐N‐acetylglucosamine deacetylase
(LpxC) inhibitors as Gram‐negative antibacterial agents, compounds containing
the hydrophobic tails with different lengths and terminal substitutions were
synthesized and their antibacterial activities against standard and clinically
isolated Gram‐negative strains were evaluated. We summarized their struc-
ture–activity relationships and found that oxazolidinone‐based compounds
exhibited a narrower antibacterial spectrum compared with threonine‐based
compounds. Furthermore, we parallelly compared the metabolic stabilities of the
compounds with the classic threonine scaffold and the novel oxazolidinone
scaffold in liver microsomes. The results indicated that the druggability of the
oxazolidinone scaffold may be inferior to the classic threonine scaffold in the
design of LpxC inhibitors.
2State Key Laboratory of Drug Research,
Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai, China
3Central Hospital affiliated to Shenyang
Medical College, Shenyang, Liaoning, China
Correspondence
Ju Liu and Ye Chen, Key Laboratory of New
Drug Research and Development of Liaoning
Province, College of Pharmacy, Liaoning
University, Shenyang, Liaoning, China.
Email: liuju1216@126.com (J. L.) and
sy-chenye@163.com (Y. C.)
Funding information
Youth Project of Education Department of
Liaoning Province, Grant/Award Number:
LQN201709; National Natural Science
Foundation of China, Grant/Award Number:
21807055
K E Y W O R D S
antibacterial activity, oxazolidine, QSAR
since the discovery of L‐161,240 (1) in 1996.[3] The X‐ray crystal
structure of LpxC from Aquifex aeolicus demonstrates the
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1
INTRODUCTION
Multi‐resistant Gram‐negative bacteria infections, especially caused
by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae,
Acinetobacter baumannii, and Pseudomonas aeruginosa have evolved
into a public health crisis recently.[1] Unfortunately, compared with
the increasing quantities of drugs against Gram‐positive bacteria
infections, only a few novel Gram‐negative antibiotics are in the
clinical development pipeline.[2] Therefore, there is an urgent need
for novel and broad‐spectrum Gram‐negative antibiotics with new
mechanisms of action and chemical classes.
existence of a catalytic zinc ion and a hydrophobic tunnel
accommodating a myristate fatty acid chain.[4,5] Thus, the classic
LpxC inhibitors are usually composed of a zinc‐binding group to
disable the catalytic zinc ion, a hydrophobic tail to mimic the
myristate in the natural substrate, and a scaffold to connect them.
The most common zinc‐binding group is hydroxamic acid, which
could exhibit the strongest binding activity to the zinc ion.[6,7] The
hydrophobic tail is usually composed of linear hydrophobic chains
with different lengths and substitutions, which is quite similar
except slight differences.[8,9] Therefore, scientists preferred to
spend more efforts to study new scaffolds to obtain a revolu-
tionary breakthrough. The oldest scaffold of LpxC inhibitors was
UDP‐3‐O‐acyl‐N‐acetylglucosamine deacetylase (LpxC) inhibi-
tors have been developed for more than 20 years as new‐type
antibacterial agents against Gram‐negative bacteria infections
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Arch Pharm Chem Life Sci. 2019;e1900129.
wileyonlinelibrary.com/journal/ardp © 2019 Deutsche Pharmazeutische Gesellschaft
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the threonine moiety, represented by CHIR‐090 (2) and LPC‐011
(3), which displayed remarkable antibacterial activity against a
wide range of Gram‐negative bacteria.[10,11] Besides, the LpxC
inhibitors consisting of other scaffolds (4, 5) also exhibit excellent
antibacterial activities, although none of them have reached the
market to our knowledge (Figure 1).[12,13]
catalyzed by Pd(PPh3)2Cl2 was carried out between intermediate A9
and phenylacetylene to afford the corresponding intermediate A10
and then converted to corresponding hydroxamic acid DD‐1 using
the aqueous solution of NH2OH.
In 2016, Kurasaki et al.[14] reported a series of oxazolidinone‐
based LpxC inhibitors, aimed to replace the threonine moiety.
These compounds, especially 6, exhibited remarkable antibacterial
activities against E. coli and K. pneumoniae, and aroused our
interest. To have a further exploration of the structure–activity
relationship and druggability of this novel scaffold, a series of
oxazolidinone‐based LpxC inhibitors were designed, synthesized,
and biologically evaluated.
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2.1.2
Method B: Synthesis of oxazolidinone‐based
LpxC inhibitors (DD‐2–DD‐5, DD‐9–DD‐10, DD‐
12–DD‐16)
The target compounds DD‐2–DD‐5, DD‐9–DD‐10, DD‐12–DD‐16
were afforded according to the procedure illustrated in Scheme 2.
The ring‐open reaction was adopted between commercially
available materials (R)‐glycidol and 4‐iodoaniline to yield dihy-
droxyl intermediate B‐02, which was further cyclized using diethyl
carbonate under alkaline condition to give oxazolidinone B‐03. The
oxidization reaction was carried to transfer hydroxyl oxazolidi-
none B‐03 to the corresponding carboxylic acid B‐04, and then
methylated to afford corresponding carboxylic ester B‐05. Inter-
mediate B‐06 was obtained by Sonogashira cross‐coupling reac-
tion catalyzed by Pd(PPh3)2Cl2 from ester B‐05 and trimethylsi-
lylacetylene, then deprotected by TBAF to get corresponding
terminal alkyne B‐07. The Suzuki coupling reaction catalyzed by
Pd(PPh3)4 was adopted to afford intermediate B‐08. The Sonoga-
shira cross‐coupling reactions catalyzed by Pd(PPh3)2Cl2 were
carried out between B‐05 and alkynes with different substitutions
to afford the corresponding intermediates B‐09–B‐11.The Eglinton
cross‐coupling reactions catalyzed by Cu(OAc)2 were carried out
separately between alkyne B‐07 and other alkynes to get
corresponding intermediates B‐12–B‐19. At last, intermediates
B‐08–B‐19 were converted to corresponding hydroxamic acids
(DD‐2–DD‐5, DD‐9–DD‐10, DD‐12–DD‐16, 23e) using the aqu-
eous solution of NH2OH.
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RESULTS AND DISCUSSION
Chemistry
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2.1
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2.1.1
Method A: Synthesis of N‐methyl
imidazolidone‐based LpxC inhibitors (DD‐1)
The target compound DD‐1 was afforded according to the procedure
illustrated in Scheme 1. (S)‐Glycidol was protected by PMBCl with
the existence of NaH to give A2. Ring‐open reaction was proceeded
using NaN3 in ethanol/H2O to afford A3, then converted to aziridine
A4 through a one‐pot process. Intermediate A5 was obtained by
another ring‐open reaction between 4‐iodoaniline and A4, followed
by self‐cyclization and methylation to yield imidazolidone A6, then
deprotected by trifluoroacetic acid to give A7. Subsequently,
oxidization and methylation reactions were proceeded successively
to get intermediate A9. The Sonogashira cross‐coupling reaction
FIGURE 1 Structures of reported UDP‐3‐O‐acyl‐N‐acetylglucosamine deacetylase inhibitors

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SCHEME 1 Reagents and conditions: (a) PMBCl, NaH, TBAI, THF; (b) NaN3, NH4Cl, EtOH/H2O; (c) PPh3, Et3N, CbzCl, acetonitrile; (d) 4‐
iodoaniline, LiClO4, acetonitrile/H2O; (e) NaH, CH3I, TBAI; (f) TFA, DCM; (g) TEMPO, NaClO, NaClO2, CH3CN/H2O; (h) CH3I, Cs2CO3, DMF; (i)
phenylacetylene, Pd(PPh3)2Cl2, CuI, TEA, THF; (j) NH2OH (50% in water), DCM/MeOH
SCHEME 2 Reagents and conditions: (a) 4‐Iodoaniline, EtOH; (b) diethyl carbonate, MeOH/MeONa, toluene; (c) TEMPO, NaClO,
NaClO2, CH3CN/H2O; (d) CH3I, Cs2CO3, DMF; (e) ethynyltrimethylsilane, Pd(PPh3)2Cl2, CuI, TEA, THF; (f) TBAF, THF; (g) alkynes,
Pd(Ph3)2Cl2, CuI, TEA, THF; (h) phenylboronic acid, Na2CO3, Pd(PPh3)4, H2O/isopropanol; (i) alkynes, Cu(OAc)2, MeOH/pyridine; (j)
NH2OH (50% in water), DCM/MeOH

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SCHEME 3 Reagents and conditions: (a) 4‐Iodophenol, DIAD, PPh3, THF; (b) mCPBA, DCM; (c) B‐07, Pd(PPh3)2Cl2, CuI, TEA, THF; (d)
NH2OH (50% in water), DCM/MeOH
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2.1.3
Method C: Synthesis of oxazolidinone‐based
2.2
Biology
LpxC inhibitors (DD‐6–DD‐7)
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2.2.1
Minimum inhibitory concentration values
The target compounds DD‐6–DD‐7 were afforded according to
the procedure illustrated in Scheme 3. The Mitsunobu reaction
was adopted between commercially available thiols C‐01–C‐02
and 4‐iodoaniline to yield ethers C‐03–C‐04, and then further
oxidized using mCPBA to give corresponding sulfones C‐05–C‐
06. Intermediates C‐07–C‐08 were obtained by Sonogashira
cross‐coupling reactions catalyzed by Pd(PPh3)2Cl2 from sulfones
C‐05–C‐06 and intermediate B‐07, and then converted to the
corresponding hydroxamic acids DD‐6–DD‐7 using the aqueous
solution of NH2OH.
The minimum inhibitory concentration (MIC) values of all tested
compounds are listed in Table 1. All of them exhibited more potent
antibacterial activities against E. coli species than P. aeruginosa species.
At first, we compared the antibacterial activity between DD‐1 and DD‐
4, because they had the same structures except the scaffold parts.
Unfortunately, DD‐1 with the N‐methyl imidazolidone scaffold showed
lower antibacterial activities against both E. coli and P. aeruginosa,
compared with the oxazolidinone‐based compound DD‐4. This result
confirms that oxazolidinone scaffold is a more appropriate structure
than imidazolidone scaffold in the design of LpxC inhibitors. Then, we
refocused our research to the oxazolidinone‐based series. The
antibacterial activities against E. coli species increased with the length
of the hydrophobic tails (DD‐2–DD‐4, DD‐9). At the same time,
compounds containing linear tails (DD‐9) showed stronger antibacterial
activities than those containing nonlinear tails (DD‐6–DD‐7). For the
compounds containing the structure of “benzene–alkyne–benzene,” the
introduction of small terminal substitutions only caused marginal
effects to their antibacterial activities (DD‐4–DD‐5, DD‐8). For the
compounds containing the structure of “benzene–alkyne–alkyne–ben-
zene”, the introduction of small terminal substitutions brought a boost
to their antibacterial activities (DD‐9–DD‐11). Then we replaced the
benzene ring of DD‐9 with aliphatic ring of different sizes and get
compounds DD‐12–DD‐13 and known compound 23e. Compound DD‐
13 exhibited strongest antibacterial activity against E. coli species, but
barely inhibited the P. aeruginosa species. The introduction of hydroxyl
to the compounds containing terminal aliphatic substitutions decreased
their antibacterial activity dramatically (DD‐13 vs. DD‐14, DD‐15 vs.
DD‐16). In conclusion, compared with classic LpxC inhibitor CHIR‐090,
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2.1.4
Method D: Synthesis of oxazolidinone‐based
LpxC inhibitors (DD‐8, DD‐11)
The target compounds DD‐8 and DD‐11 were afforded according to
the procedure illustrated in Scheme 4. The nucleophilic substitution
was adopted between methylamine and intermediate D‐01 to yield
sulfamide D‐02, then coupled with ethynyltrimethylsilane by Sono-
gashira cross‐coupling reaction catalyzed by Pd(PPh3)2Cl2 to afford
D‐03. Subsequently, the deprotection reaction was proceeded under
alkaline condition to give terminal alkyne D‐04. The Sonogashira
cross‐coupling reaction catalyzed by Pd(PPh3)2Cl2 and the Eglinton
cross‐coupling reaction catalyzed by Cu(OAc)2 were carried out
separately between intermediate D‐04 and oxazolidinone‐based
intermediates (B‐05, B‐07) to give intermediates D‐05–D‐06, which
were converted to corresponding hydroxamic acids DD‐8 and DD‐11
using the aqueous solution of NH2OH.
SCHEME 4 Reagents and conditions: (a) Methylamine, DCM; (b) ethynyltrimethylsilane, Pd(PPh3)2Cl2, CuI, DIEA, THF; (c) K2CO3, MeOH; (d)
B‐05, Pd(PPh3)2Cl2, CuI, TEA, THF; (d) B‐07, Cu(OAc)2, MeOH/pyridine; (f) NH2OH (50% in water), DCM/MeOH

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TABLE 1 In vitro antibacterial activities of compounds against the Escherichia coli species and the Pseudomonas aeruginosa species
MIC (μg/ml)
Compound
X
R
E. colia
E. colib
P. aeruginosac
P. aeruginosad
DD‐1
N–CH3
20
20
>256
>256
DD‐2
O
50
50
200
200
DD‐3
DD‐4
O
O
50
50
>256
10
>256
10
1.25
0.625
DD‐5
DD‐6
O
O
1.25
50
0.625
50
10
10
125
125
DD‐7
DD‐8
O
O
6.25
3.12
6.25
6.25
>256
>256
>256
>256
DD‐9
O
O
O
0.12
0.31
100
100
DD‐10
DD‐11
0.020
0.078
0.025
0.078
100
100
>256
>256
DD‐12
DD‐13
DD‐14
O
O
O
0.62
0.015
1.56
0.78
0.020
1.56
>256
>256
>256
>256
>256
>256
DD‐15
DD‐16
O
O
0.156
3.12
0.156
3.12
25
25
>256
>256
23e
O
0.03
0.04
100
2.5
100
2.5
CHIR‐090
–
–
0.156
0.156
Abbreviation: MIC, minimum inhibitory concentration.
aE. coli, DH5α.
bE. coli, AB1157.
cP. aeruginosa, PAO1.
dP. aeruginosa, PA14.
oxazolidinone compounds DD‐9–DD‐10, DD‐13 and known compound
23e exhibit improved antibacterial activity against E. coli species and
declined antibacterial activity against P. aeruginosa species.
similar antibacterial activities to CHIR‐090 and much stronger
antibacterial activities than aztreonam. For multidrug‐resistant E.
cloacae, the oxazolidinone‐based compounds (DD‐10, 23e) exhibited
similar antibacterial activities to CHIR‐090, and weaker antibacterial
activities than aztreonam. For multidrug‐resistant A. baumannii, all of
these compounds exhibited weak inhibitory activities. For multidrug‐
resistant and standard P. aeruginosa, the antibacterial activities of
oxazolidinones (DD‐10, 23e) were slightly weaker than aztreonam, but
much weaker than CHIR‐090.
To further explore the antibacterial activities and spectrum of this
novel series, compounds DD‐10 and 23e were selected to experiment
with clinical isolated multidrug‐resistant strains. Meanwhile, CHIR‐090
and aztreonam were also selected as control drugs. Their MIC values
are listed in Table 2. For E. coli and multidrug‐resistant K. pneumoniae,
compounds containing oxazolidinone scaffold (DD‐10, 23e) exhibited

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TABLE 2 In vitro antibacterial activities of compounds against clinical isolated strains
MIC (μg/ml)
Compound
DD‐10
E. colia
K. pneumoniaeb
E. cloacaec
A. baumanniid
P. aeruginosae
16
P. aeruginosaf
≤0.125–1
≤0.125–2
≤0.125–0.5
1 to >16
0.25–8
0.5–2
≥16
16
16
2
23e
≤0.125–1
0.25–1
0.25–2
8–16
8–16
CHIR‐090
Aztreonam
0.25–1
4–16
0.25–1
4–16
≥16
≤0.25–0.5
≥16
4
Abbreviation: MIC, minimum inhibitory concentration.
aE. coli, 5 strains.
bMultidrug‐resistant K. pneumoniae, 5 strains.
cMultidrug‐resistant E. cloacae, 5 strains.
dMultidrug‐resistant A. baumannii, 5 strains.
eMultidrug‐resistant P. aeruginosa, 5 strains.
fP. aeruginosa, ATCC 27853.
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2.2.2
Stabilities in the liver microsomes
Avance III 500. Spectra were given in ppm (δ) and coupling
constants, J values, were reported in hertz. Splitting patterns were
designated as follows: s, singlet; brs, broad singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. Tetramethylsilane was used as an
internal reference standard. Mass spectra were obtained on a
Finnigan MAT95 spectrometer (EI‐MS) or Finnigan LCQ‐DECA
spectrometer (ESI‐MS). High resolution mass spectrum was
obtained on a Micromass Ultra Q‐TOF spectrometer (ESI‐MS).
HPLC techniques (Agilent 1100 series) were used to determine the
purity of compounds. All reagents and solvents were obtained from
commercial suppliers and used without further purifcation. Room
temperature refers to 20–25°C. All reaction mixtures were
monitored using thin‐layer chromatography (TLC) on silica gel F‐
254 TLC plates. All products, unless otherwise noted, were purified
by column chromatography using silica gel (200–300 mesh). All final
compounds were purified to >95% purity as determined by an
Agilent 1100 series LC system (PLATISIL ODS 5 μm 250 × 4.6 mm)
with two solvent systems (acetonitrile/water or acetonitrile/buffer
[0.1% CF3COOH in water]). The following abbreviations are used:
deuterated chloroform; petroleum ether; ethyl acetate (EtOAc);
dichloromethane (DCM); N,N‐dimethylformamide (DMF); magne-
sium sulfate; tetrahydrofuran (THF); ammonium chloride (NH4Cl);
methanol (MeOH); sodium bicarbonate (NaHCO3); trifluoroacetic
acid (TFA); sodium azide (NaN3); tetrabutylammonium iodide
(TBAI); lithium perchlorate (LiClO4); 2,2,6,6‐tetramethylpiperidi-
nooxy (TEMPO); sodium chlorite (NaClO2) solution; sodium hypo-
chlorite (NaClO); bis(triphenylphosphine)palladium(II) chloride
Moreover, to study the metabolism characters of the novel
oxazolidinone‐based series, compounds 23e and YDL‐2 (synthesized
according to published procedures[7]) were selected to parallelly test
their metabolism stabilities in liver microsomes of different species.[8]
The results are listed in Table 3. Compound 23e, containing the
oxazolidinone scaffold, exhibited much weaker metabolism stability
than YDL‐2 containing the threonine scaffold in all species.
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3
CONCLUSION
In summary, the compounds containing novel oxazolidinone scaffold
exhibit a narrower antibacterial spectrum and worse biological
metabolism stability in liver microsomes compared with the
compounds containing the threonine scaffold, which indicated that
the oxazolidinone scaffold may be inferior to the threonine scaffold
in the design of LpxC inhibitors.
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4
EXPERIMENTAL
Chemistry
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4.1
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4.1.1
General
Proton nuclear magnetic resonance spectra were obtained on a
Bruker Biospin Avance III 400 spectrometer or Bruker Biospin
TABLE 3 Half‐lives and intrinsic clearances of oxazolidinone‐based compound and threonine‐based compound
Compound
23e
Structure
Species
Human
Rat
Microsomal t1/2, min
Clint, (ml·min−1·g−1·protein)
46
21
41
46
99
51
Mouse
YDL‐2
Human
Rat
632.6
189.5
904.1
3
11
2
Mouse

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(Pd(PPh3)2Cl2); tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4);
cupric acetate (Cu(OAc)2); diisopropyl azodiformate (DIAD);
triphenylphosphine (PPh3); tetrabutylammonium fluoride (TBAF); 3‐
chloroperoxybenzoic acid (mCPBA).
Benzyl (S)‐{1‐[(4‐iodophenyl)amino]‐3‐[(4‐methoxybenzyl)oxy]pro-
pan‐2‐yl}carbamate (A‐05)
Step (d). Intermediate A‐04 (2.2 g, 6.7 mmol) was dissolved in the
mixed solvent of acetonitrile (80 ml) and water (20 ml), then LiClO4
(1.1 g, 10 mmol) and 4‐iodoaniline (2.2 g, 10 mmol) were added. The
resulting solution was stirred for 10 hr at 95℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 2.6 g (71%) of A‐04 as a yellow liquid. 1H NMR (400 MHz,
chloroform‐d) δ 7.52–7.26 (m, 8H), 7.23 (d, J = 8.7 Hz, 2H), 6.89 (d,
J = 8.8 Hz, 2H), 6.37 (d, J = 8.5 Hz, 2H), 5.09 (s, 2H), 4.54–4.35 (m,
2H), 3.82 (s, 3H), 3.65–3.41 (m, 4H), 3.27 (d, J = 6.4 Hz, 2H). MS (EI)
m/z: (M+, 546).
The original NMR spectra of the investigated compounds are
provided as Supporting Information, as are their InChI codes
together with some biological activity data.
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4.1.2
Compounds synthesized by Method A
(Scheme 1)
(R)‐2‐{[(4‐Methoxybenzyl)oxy]methyl}oxirane (A‐02)
Step (a). NaH (60% dispersion in mineral oil, 0.65 g) was dispersed in
the dry DMF (40 ml) under argon protection at 0℃; then A‐01
(1.7 g, 11 mmol) and TBAI (0.5 g, 1.4 mmol) were added. The
resulting solution was stirred for 8 hr at room temperature and
monitored by TLC. Water was added, and it was extracted with
EtOAc. The organic phase was washed with saturated NH4Cl
solution and brine, dried over anhydrous Na2SO4, and filtered, and
then the filtrate was concentrated in vacuo. The residue was
purified by chromatography to give 1.4 g (83%) of A‐02 as a
(S)‐1‐(4‐Iodophenyl)‐4‐{[(4‐methoxybenzyl)oxy]methyl}‐3‐methylimi-
dazolidin‐2‐one (A‐06, Scheme 1)
Step (e). NaH (60% dispersion in mineral oil, 66 mg) was dispersed
in 40 ml of dry DMF under argon protection at 0℃, then A‐05
(0.15 g, 0.28 mmol) and TBAI (10 mg, 0.03 mmol) were added. The
resulting solution was stirred for 8 hr at room temperature. After
that, CH3I (78 mg, 0.55 mmol) was added, and the mixed solution
was stirred for 8 hr and monitored by TLC. The posttreatment
process was the same as Step (a) in method A to give 0.11 g (85%)
of A‐06 as a white solid. 1H NMR (400 MHz, chloroform‐d) δ 7.59
(d, J = 9.1 Hz, 2H), 7.33 (d, J = 9.2 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H),
6.89 (d, J = 8.7 Hz, 2H), 4.49 (s, 2H), 3.86–3.79 (m, 4H), 3.79–3.69
(m, 1H), 3.61 (dd, J = 9.6, 4.6 Hz, 1H), 3.51 (dt, J = 8.7, 5.6 Hz, 2H),
2.88 (s, 3H). MS (EI) m/z: (M+, 452).
colorless liquid. 1H NMR (400 MHz, chloroform‐d)
δ 7.30 (d,
J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 4.54 (q, J = 11.5 Hz, 2H),
3.83 (s, 3H), 3.76 (dd, J = 11.4, 3.1 Hz, 1H), 3.44 (dd, J = 11.4, 5.8 Hz,
1H), 3.20 (ddt, J = 5.7, 3.8, 2.9 Hz, 1H), 2.82 (dd, J = 5.0, 4.1 Hz, 1H),
2.63 (dd, J = 5.0, 2.7 Hz, 1H). MS (EI) m/z: (M+, 194).
(R)‐1‐Azido‐3‐[(4‐methoxybenzyl)oxy]propan‐2‐ol (A‐03)
Step (b). Intermediate A‐02 (0.90 g, 6.0 mmol) was dissolved in the
mixed solvent of ethanol (30 ml) and water (80 ml). Then NaN3
(0.84 g, 13 mmol) and NH4Cl (0.75 g, 14 mmol) were added. The
resulting solution was stirred for 10 hr at 100℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 1.9 g (74%) of A‐03 as a colorless liquid. 1H NMR (400 MHz,
chloroform‐d) δ 7.33–7.10 (m, 2H), 6.97–6.82 (m, 2H), 4.51 (s, 2H),
4.05–3.92 (m, 1H), 3.83 (s, 3H), 3.59–3.46 (m, 2H), 3.41–3.30 (m, 2H),
2.48 (d, J = 5.3 Hz, 1H). MS (EI) m/z: (M+, 237).
(S)‐4‐(Hydroxymethyl)‐1‐(4‐iodophenyl)‐3‐methylimidazolidin‐2‐one
(A‐07)
Step (f). Intermediate A‐06 (0.35 g, 0.77 mmol) was dissolved in the
mixed solvent of DCM (10 ml) and TFA (3.0 ml), and the resulting
solution was stirred for 15 hr at room temperature and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 0.22 g (86%) of A‐07 as a white solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.62 (d, J = 9.1 Hz, 2H), 7.38 (d, J = 9.1 Hz, 2H),
3.94–3.83 (m, 2H), 3.80–3.68 (m, 3H), 2.94 (s, 3H), 2.27–2.22 (m, 1H).
MS (EI) m/z: (M+, 332).
Benzyl (S)‐2‐{[(4‐methoxybenzyl)oxy]methyl}aziridine‐1‐carboxylate
(A‐04)
Step (c). Intermediate A‐03 (1.9 g, 8.0 mmol) was dissolved in the
dry acetonitrile (80 ml) under argon protection at room tempera-
ture; then triphenylphosphine (2.1 g, 8.0 mmol) was added. The
resulting solution was stirred for 6 hr at 70℃ and then warmed to
room temperature. After that, triethylamine (1.2 g, 12 mmol) and
benzyl chloroformate (1.6 g, 9.6 mmol) were added, and the mixed
solution was stirred for 2 hr and monitored by TLC. The posttreat-
ment process was the same as Step (a) in method A to give 2.2 g
(84%) of A‐04 as a colorless liquid. 1H NMR (400 MHz, chloroform‐
d) δ 7.37 (s, 5H), 7.24 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.15
(s, 2H), 4.60–4.38 (m, 2H), 3.82 (s, 3H), 3.61 (d, J = 4.7 Hz, 2H),
2.76–2.70 (m, 1H), 2.37 (d, J = 6.1 Hz, 1H), 2.22 (d, J = 3.7 Hz, 1H).
MS (EI) m/z: (M+, 327).
(S)‐1‐(4‐Iodophenyl)‐3‐methyl‐2‐oxoimidazolidine‐4‐carboxylic acid
(A‐08)
Step (g). Intermediate A‐07 (0.22 g, 0.66 mmol) was dissolved in the
mixed solvent of acetonitrile (16 ml) and phosphate buffer (pH 6.7,
3.0 mL), then TEMPO (26 mg, 0.16 mmol), NaClO2 solution (0.60 g in
6.0 ml H2O), NaClO solution (0.10 g in 2.0 ml H2O) were added. The
resulting solution was stirred for 15 hr at 80℃ and monitored by
TLC. Then diluted hydrochloric acid (1 N) was added to adjust the pH
value to 1–2. The post‐treatment process was the same as Step (a) in
method A. The concentrated product was used to the next step
without any further purification. MS (EI) m/z: (M+, 346).

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Methyl (S)‐1‐(4‐iodophenyl)‐3‐methyl‐2‐oxoimidazolidine‐4‐carboxy-
late (A‐09)
J = 13.0, 5.6 Hz, 1H), 2.86 (dt, J = 12.2, 5.8 Hz, 1H). MS (ESI) m/z:
[(M–H)−, 291.8].
Step (h). Intermediate A‐08 (obtained by the last step) was dissolved
in the dry DMF (10 ml); then Cs2CO3 (0.22 g, 0.66 mmol) and CH3I
(0.24 g, 1.7 mmol) were added. The resulting solution was stirred for
12 hr at room temperature and monitored by TLC. The post‐
treatment process was the same as Step (a) in method A to give
0.12 g (50%, for two steps) of A‐09 as a white solid. 1H NMR
(400 MHz, chloroform‐d) δ 7.63 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz,
2H), 4.25 (dd, J = 10.1, 5.2 Hz, 1H), 4.06 (t, J = 9.8 Hz, 1H), 3.85 (m,
4H), 2.99 (s, 3H). MS (EI) m/z: (M+, 360).
(S)‐5‐(Hydroxymethyl)‐3‐(4‐iodophenyl)oxazolidin‐2‐one (B‐03)
Step (b). Intermediate B‐02 (2.4 g, 8.1 mmol) was dissolved in the
anhydrous methylbenzene (80 ml), then diethyl carbonate (2.9 g,
24 mmol) and sodium methanolate (30% in methanol, 1.5 ml) were
added under argon protection. The resulting solution was stirred for
8 hr at 105℃ and monitored by TLC. The posttreatment process was
the same as Step (a) in method A to give 1.8 g (68%) of B‐03 as a
white solid. 1H NMR (400 MHz, DMSO‐d6) δ 7.72 (d, J = 9.2 Hz, 2H),
7.42 (d, J = 8.8 Hz, 2H), 5.23 (t, J = 5.6 Hz, 1H), 4.70 (ddt, J = 9.5, 6.4,
3.6 Hz, 1H), 4.06 (t, J = 9.0 Hz, 1H), 3.80 (dd, J = 8.8, 6.2 Hz, 1H),
3.71–3.64 (m, 1H), 3.55 (dt, J = 12.3, 4.9 Hz, 1H). MS (ESI) m/z:
[(M–H)–, 317.5].
Methyl (S)‐3‐methyl‐2‐oxo‐1‐[4‐(phenylethynyl)phenyl]imidazolidine‐
4‐carboxylate (A‐10)
Step (i). Intermediate A‐09 (88 mg, 0.22 mmol) was dissolved in the
dry THF (10 ml), then TEA (74 mg, 0.73 mmol), Pd(PPh3)2Cl2 (17 mg,
0.024 mmol), CuI (3.0 mg, 0.012 mmol), phenylacetylene (50 mg,
0.49 mmol) were added under argon protection at room temperature.
The resulting solution was stirred for 12 hr at 80℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 73 mg (89%) of A‐10 as a yellow solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.67–7.45 (m, 6H), 7.43–7.30 (m, 3H), 4.27 (dd,
J = 10.0, 5.0 Hz, 1H), 4.12 (t, J = 9.7 Hz, 1H), 3.91 (dd, J = 9.5, 5.2 Hz,
1H), 3.86 (s, 3H), 3.01 (s, 3H). MS (EI) m/z: (M+, 334).
(S)‐3‐(4‐Iodophenyl)‐2‐oxooxazolidine‐5‐carboxylic acid (B‐04)
Step (c). Intermediate B‐03 (0.37 g, 1.1 mmol) was dissolved in the
mixed solvent of acetonitrile (16 ml) and phosphate buffer (pH 6.7,
3.0 ml), then TEMPO (26 mg, 0.16 mmol), NaClO2 solution (0.60 g in
6.0 ml H2O), NaClO solution (0.10 g in 2.0 ml H2O) were added. The
resulting solution was stirred for 15 hr at 80℃ and monitored by
TLC. Then diluted hydrochloric acid (1 N) was added to adjust the pH
value to 1–2. The posttreatment process was the same as Step (a) in
method A. The concentrated product was used to the next step
without any further purification. MS (EI) m/z: (M+, 333).
(S)‐N‐Hydroxy‐3‐methyl‐2‐oxo‐1‐[4‐(phenylethynyl)phenyl]imidazoli-
dine‐4‐carboxamide (DD‐1)
Step (j). Intermediate A‐10 (70 mg, 0.21 mmol) was dissolved in the
mixed solvent of DCM (6.0 ml) and MeOH (2.0 ml), then hydro-
xylamine (50% in water) was added. The resulting solution was
stirred for 6 hr at room temperature and monitored by TLC, then
concentrated in vacuo. The residue was washed by DCM three times
and dried to give 50 mg (71%) of DD‐1 as a white solid. 1H NMR
(400 MHz, DMSO‐d6) δ 7.64 (d, J = 8.7 Hz, 2H), 7.59–7.47 (m, 4H),
7.45–7.29 (m, 3H), 4.09–3.94 (m, 2H), 3.68 (dd, J = 6.4, 2.3 Hz, 1H),
2.70 (s, 3H). 13C NMR (126 MHz, DMSO‐d6) δ 166.14, 156.92,
141.13, 132.45 (overlap), 131.65 (overlap), 129.18 (overlap), 128.91,
123.11, 116.80 (overlap), 115.28, 90.13, 88.83, 54.82, 45.75, 29.51.
MS(ESI) m/z: [(M+H)+, 336.0]. HRMS (ESI): Anal. calc. for
Methyl (S)‐3‐(4‐iodophenyl)‐2‐oxooxazolidine‐5‐carboxylate (B‐05)
Step (d). Intermediate B‐04 (obtained by the last step) was dissolved
in the dry DMF (10 ml), then Cs2CO3 (0.41 g, 1.3 mmol) and CH3I
(0.24 g, 1.7 mmol) were added. The resulting solution was stirred for
12 hr at room temperature and monitored by TLC. The post‐
treatment process was the same as Step (a) in method A to give
0.30 g (75%, for two steps) of B‐05 as a white solid. 1H NMR
(400 MHz, chloroform‐d) δ 7.70 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.5 Hz,
2H), 5.09 (dd, J = 9.5, 5.3 Hz, 1H), 4.29 (t, J = 9.4 Hz, 1H), 4.13 (dd,
J = 9.1, 5.3 Hz, 1H), 3.89 (s, 3H). MS (ESI) m/z: [(M+H)+, 348.0].
C19H18O3N3: 336.1348, found: 336.1339.
Methyl (S)‐2‐oxo‐3‐{4‐[(trimethylsilyl)ethynyl]phenyl}oxazolidine‐5‐
carboxylate (B‐06)
|
4.1.3
Compounds synthesized by Method B
(Scheme 2)
Step (e). Intermediate B‐05 (1.3 g, 3.7 mmol) was dissolved in the dry
THF (10 ml), then TEA (1.5 g, 15 mmol), Pd(PPh3)2Cl2 (0.22 g,
0.31 mmol), CuI (60 mg, 0.31 mmol), trimethylsilylacetylene (0.31 g,
3.1 mmol) were added under argon protection at room temperature.
The resulting solution was stirred for 12 hr at 80℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 1.1 g (93%) of B‐06 as a yellow solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.47 (s, 4H), 5.06 (dd, J = 9.7, 5.3 Hz, 1H), 4.28 (dd,
J = 9.7, 9.3 Hz, 1H), 4.13 (dd, J = 9.3, 5.3 Hz, 1H), 3.86 (s, 3H), 0.24 (s,
9H). MS (ESI) m/z: [(M+H)+, 318.3].
(S)‐3‐[(4‐Iodophenyl)amino]propane‐1,2‐diol (B‐02)
Step (a). 4‐Iodoaniline (2.5 g, 12 mmol) was dissolved in the
anhydrous EtOH (30 ml), then intermediate B‐01 was added under
argon protection. The resulting solution was stirred for 12 hr at 75℃
and monitored by TLC. The posttreatment process was the same as
Step (a) in method A to give 2.5 g (81%) of B‐02 as a white solid. 1H
NMR (400 MHz, DMSO‐d6) δ 7.31 (d, J = 8.5 Hz, 2H), 6.45 (d,
J = 8.6 Hz, 2H), 5.72 (t, J = 5.8 Hz, 1H), 4.77 (d, J = 4.9 Hz, 1H), 4.60
(t, J = 5.6 Hz, 1H), 3.60 (h, J = 5.6 Hz, 1H), 3.43–3.32 (m, 2H), 3.12 (dt,

DING ET AL.
9 of 13
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Methyl (S)‐3‐(4‐ethynylphenyl)‐2‐oxooxazolidine‐5‐carboxylate
(B‐07)
(m, 1H), 0.90–0.84 (m, 2H), 0.83–0.76 (m, 2H). MS (ESI) m/z: [(M+H)+,
286.1].
Step (f). Intermediate B‐06 (0.30 g, 0.95 mmol) was dissolved in the
dry THF (10 ml), then TBAF (1.0 M in THF, 1.0 ml) was added at 0℃.
The resulting solution was stirred for 10 min at room temperature
and monitored by TLC. The posttreatment process was the same as
Step (a) in method A to give 80 mg (34%) of B‐07 as a white solid. 1H
NMR (400 MHz, chloroform‐d) δ 7.50 (s, 4H), 5.08 (dd, J = 9.6, 5.3 Hz,
1H), 4.29 (t, J = 9.5 Hz, 1H), 4.15 (dd, J = 9.3, 5.3 Hz, 1H), 3.87 (s, 3H),
3.07 (s, 1H). MS (ESI) m/z: [(M+K)+, 284.1].
(S)‐3‐[4‐(Cyclopropylethynyl)phenyl]‐N‐hydroxy‐2‐oxooxazolidine‐5‐
carboxamide (DD‐3)
Compound DD‐3 was prepared from intermediate B‐09 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.21 (s, 1H), 9.27 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.38 (d,
J = 8.4 Hz, 2H), 4.97 (dd, J = 9.2, 5.0 Hz, 1H), 4.26 (t, J = 9.2 Hz, 1H),
4.05–3.96 (m, 1H), 1.53 (p, J = 6.8 Hz, 1H), 1.02–0.79 (m, 2H),
0.75–0.64 (m, 2H). 13C NMR (126 MHz, DMSO‐d6) δ 164.92, 153.87,
137.86, 132.45 (overlap), 118.66, 118.15 (overlap), 93.84, 75.65,
69.43, 47.60, 8.81, 0.24. MS (ESI) m/z: [(M−H)−, 284.9]. HRMS (ESI):
Anal. calc. for C15H13O4N2: 285.0881, found: 285.0881.
Methyl (S)‐3‐([1,1′‐biphenyl]‐4‐yl)‐2‐oxooxazolidine‐5‐carboxylate
(B‐08)
Step (h). Intermediate B‐07 (0.20 g, 0.58 mmol) was dissolved in the
mixed solvent of isopropanol (10 ml) and H2O (3.0 ml), then Na2CO3
(0.12 g, 1.2 mmol), Pd(PPh3)4 (33 mg, 0.029 mmol), phenylboronic
acid (0.31 g, 3.1 mmol) were added under argon protection at room
temperature. The resulting solution was stirred for 12 hr at 70℃ and
monitored by TLC. The posttreatment process was the same as Step
(a) in method A to give 90 mg (53%) of B‐08 as a white solid. 1H NMR
(400 MHz, DMSO‐d6) δ 7.73 (d, J = 8.6 Hz, 2H), 7.69–7.64 (m, 4H),
7.46 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.1 Hz, 1H), 5.36 (dd, J = 9.8, 5.1 Hz,
1H), 4.43 (t, J = 9.6 Hz, 1H), 4.22 (dd, J = 9.3, 5.1 Hz, 1H), 3.78 (s, 3H).
MS (ESI) m/z: [(M+Na)+, 320.0].
Methyl (S)‐2‐oxo‐3‐[4‐(phenylethynyl)phenyl]oxazolidine‐5‐carboxy-
late (B‐10)
Intermediate B‐10 was prepared from intermediate B‐05 and
phenylacetylene in the same manner as described for intermediate
B‐09. 1H NMR (400 MHz, chloroform‐d) δ 7.47–7.35 (m, 4H), 5.07
(dd, J = 9.6, 5.3 Hz, 1H), 4.28 (t, J = 9.5 Hz, 1H), 4.13 (dd, J = 9.3,
5.4 Hz, 1H), 3.87 (s, 3H), 1.48–1.38 (m, 1H), 0.90–0.84 (m, 2H),
0.83–0.76 (m, 2H). MS (ESI) m/z: [(M+H)+, 286.1].
(S)‐N‐Hydroxy‐2‐oxo‐3‐[4‐(phenylethynyl)phenyl]oxazolidine‐5‐car-
boxamide (DD‐4)
(S)‐3‐([1,1′‐Biphenyl]‐4‐yl)‐N‐hydroxy‐2‐oxooxazolidine‐5‐carboxa-
mide (DD‐2)
Compound DD‐4 was prepared from intermediate B‐10 in the same
manner as described for compound DD‐2. 1H NMR (500 MHz,
DMSO‐d6) δ 9.78 (s, 1H), 7.65–7.56 (m, 4H), 7.55–7.52 (m, 2H),
7.44–7.35 (m, 3H), 4.97 (dd, J = 9.3, 5.4 Hz, 1H), 4.28 (t, J = 9.2 Hz,
1H), 4.03 (dd, J = 9.1, 5.5 Hz, 1H). 13C NMR (126 MHz, DMSO‐d6) δ
164.82, 153.91, 138.73, 132.63 (overlap), 131.75 (overlap), 129.23
(overlap), 129.17, 122.81, 118.23 (overlap), 117.53, 89.54, 89.47,
69.53, 47.61. MS(ESI) m/z: [(M–H)–, 321.0]. HRMS (ESI): Anal. calc. for
Step (j). Intermediate B‐08 (60 mg, 0.20 mmol) was dissolved in the
mixed solvent of DCM (3.0 ml) and MeOH (1.0 ml), then hydro-
xylamine (50% in water, 1.0 ml) was added. The resulting solution
was stirred for 6 hr at room temperature and monitored by TLC, then
concentrated in vacuo. The residue was washed by DCM three times
and dried to give 40 mg (66%) of DD‐2 as a white solid. 1H NMR
(400 MHz, DMSO‐d6) δ 7.78–7.58 (m, 6H), 7.44 (t, J = 7.7 Hz, 2H),
7.33 (t, J = 7.3 Hz, 1H), 4.95 (dd, J = 9.3, 5.6 Hz, 1H), 4.28 (t, J = 9.1 Hz,
1H), 4.05 (dd, J = 9.0, 5.6 Hz, 1H). 13C NMR (126 MHz, DMSO‐d6) δ
164.83, 154.16, 139.80, 137.94, 135.73, 129.41 (overlap), 127.70,
127.56 (overlap), 126.82 (overlap), 118.74 (overlap), 69.85, 47.77.
MS (ESI) m/z: [(M–H)–, 296.9]. HRMS (ESI): Anal. calc. for
C16H15O4N2: 299.1032, found: 299.1027.
C18H13O4N2: 321.0875, found: 321.0882.
Methyl (S)‐3‐{4‐[(4‐aminophenyl)ethynyl]phenyl}‐2‐oxooxazolidine‐5‐
carboxylate (B‐11)
Intermediate B‐11 was prepared from intermediate B‐05 and 4‐
ethynylaniline in the same manner as described for intermediate
B‐09. 1H NMR (400 MHz, chloroform‐d)
δ 7.53 (s, 4H), 7.35
(d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.10 (dd, J = 9.6, 5.3 Hz,
1H), 4.33 (t, J = 9.4 Hz, 1H), 4.18 (dd, J = 9.2, 5.3 Hz, 1H), 3.90 (s, 3H).
MS (ESI) m/z: [(M+H)+, 337.0].
Methyl (S)‐3‐[4‐(cyclopropylethynyl)phenyl]‐2‐oxooxazolidine‐5‐car-
boxylate (B‐09)
Step (g). Intermediate B‐05 (78 mg, 0.22 mmol) was dissolved in the
dry THF (10 ml), then TEA (74 mg, 0.73 mmol), Pd(PPh3)2Cl2 (17 mg,
0.024 mmol), CuI (3.0 mg, 0.012 mmol), cyclopropylacetylene (32 mg,
0.49 mmol) were added under argon protection at room temperature.
The resulting solution was stirred for 12 hr at 80℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 50 mg (78%) of B‐09 as a yellow solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.47–7.35 (m, 4H), 5.07 (dd, J = 9.6, 5.3 Hz, 1H), 4.28
(t, J = 9.5 Hz, 1H), 4.13 (dd, J = 9.3, 5.4 Hz, 1H), 3.87 (s, 3H), 1.48–1.38
(S)‐3‐{4‐[(4‐Aminophenyl)ethynyl]phenyl}‐N‐hydroxy‐2‐oxooxazoli-
dine‐5‐carboxamide (DD‐5)
Compound DD‐5 was prepared from intermediate B‐11 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.22 (s, 1H), 9.28 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.48 (d,
J = 8.7 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.55 (d, J = 8.5 Hz, 2H), 5.57 (s,
2H), 4.99 (dd, J = 9.3, 5.5 Hz, 1H), 4.29 (t, J = 9.2 Hz, 1H), 4.04 (dd,
J = 9.2, 5.5 Hz, 1H). 13C NMR (126 MHz, DMSO‐d6) δ 164.91, 153.89,

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DING ET AL.
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149.89, 137.81, 132.94 (overlap), 132.01 (overlap), 118.88, 118.24
(overlap), 114.08 (overlap), 108.61, 91.40, 86.59, 69.45, 47.63. MS
(ESI) m/z: [(M–H)–, 335.9]. HRMS (ESI): Anal. calc. for C18H14O4N3:
336.0984, found: 336.0979.
Methyl (S)‐3‐[4‐(cyclohexylbuta‐1,3‐diyn‐1‐yl)phenyl]‐2‐oxooxazoli-
dine‐5‐carboxylate (B‐14)
Intermediate B‐14 was prepared from intermediate B‐07 and
cyclohexylacetylene in the same manner as described for inter-
mediate B‐12. 1H NMR (400 MHz, chloroform‐d) δ 7.51 (s, 4H), 5.10
(dd, J = 9.6, 5.2 Hz, 1H), 4.31 (t, J = 9.5 Hz, 1H), 4.16 (dd, J = 9.3,
5.3 Hz, 1H), 3.90 (s, 3H), 2.57 (tt, J = 8.9, 3.8 Hz, 1H), 1.92–1.79 (m,
2H), 1.80–1.68 (m, 2H), 1.57–1.47 (m, 3H), 1.38–1.32 (m, 3H). MS
(ESI) m/z: [(M+H)+, 352.1].
Methyl (S)‐2‐oxo‐3‐[4‐(phenylbuta‐1,3‐diyn‐1‐yl)phenyl]oxazolidine‐
5‐carboxylate (B‐12)
Intermediate B‐07 (90 mg, 0.36 mmol) was dissolved in the mixed
solvent of MeOH (3.0 ml) and pyridine (3.0 ml), then phenylacetylene
(74 mg, 0.73 mmol), Cu(OAc)2 (0.53 g, 2.9 mmol) were added under
argon protection at room temperature. The resulting solution was
stirred for 18 hr at room temperature and monitored by TLC. The
posttreatment process was the same as Step (a) in method A to give
40 mg (32%) of B‐12 as a white solid. 1H NMR (400 MHz, DMSO‐d6) δ
7.71–7.55 (m, 6H), 7.54–7.39 (m, 3H), 5.36 (dd, J = 9.8, 5.1 Hz, 1H),
4.41 (t, J = 9.7 Hz, 1H), 4.21 (dd, J = 9.4, 5.1 Hz, 1H), 3.76 (s, 3H). MS
(ESI) m/z: [(M+H)+, 345.1].
(S)‐3‐[4‐(Cyclohexylbuta‐1,3‐diyn‐1‐yl)phenyl]‐N‐hydroxy‐2‐oxooxa-
zolidine‐5‐carboxamide (DD‐12)
Compound DD‐12 was prepared from intermediate B‐14 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.22 (s, 1H), 9.27 (s, 1H), 7.60 (q, J = 8.9 Hz, 4H), 5.33 (t,
J = 4.8 Hz, 1H), 4.99 (dd, J = 9.3, 5.5 Hz, 1H), 4.28 (t, J = 9.3 Hz, 1H),
4.04 (dd, J = 9.3, 5.5 Hz, 1H), 1.83–1.75 (m, 2H), 1.68–1.59 (m, 2H),
1.53–1.40 (m, 4H), 1.36–1.28 (m, 4H). MS (ESI) m/z: [(M–H)–, 350.9].
HRMS (ESI): Anal. calc. for C20H21O4N2: 353.1496, found: 353.1487.
(S)‐N‐Hydroxy‐2‐oxo‐3‐[4‐(phenylbuta‐1,3‐diyn‐1‐yl)phenyl]oxazoli-
dine‐5‐carboxamide (DD‐9)
Methyl (S)‐3‐[4‐(cyclopentylbuta‐1,3‐diyn‐1‐yl)phenyl]‐2‐oxooxazoli-
dine‐5‐carboxylate (B‐15)
Compound DD‐9 was prepared from intermediate B‐12 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.23 (s, 1H), 9.29 (s, 1H), 7.80–7.53 (m, 6H), 7.48–7.33
(m, 3H), 5.00 (dd, J = 9.1, 5.3 Hz, 1H), 4.29 (t, J = 9.2 Hz, 1H), 4.05 (dd,
J = 9.1, 5.3 Hz, 1H). 13C NMR (126 MHz, DMSO‐d6) δ 164.82, 153.84,
139.71, 133.81 (overlap), 132.83 (overlap), 130.42, 129.39 (overlap),
120.95, 118.29 (overlap), 115.49, 82.22, 74.11, 73.74, 69.53, 47.59.
MS (ESI) m/z: [(M–H)–, 344.8]. HRMS (ESI): Anal. calc. for
C20H15O4N2: 347.1032, found: 347.1022.
Intermediate B‐15 was prepared from intermediate B‐07 and
cyclopentylacetylene in the same manner as described for inter-
mediate B‐12. 1H NMR (400 MHz, chloroform‐d) δ 7.50 (s, 4H), 5.10
(dd, J = 9.6, 5.2 Hz, 1H), 4.31 (t, J = 9.5 Hz, 1H), 4.16 (dd, J = 9.3,
5.3 Hz, 1H), 3.89 (s, 3H), 2.85–2.74 (m, 1H), 2.07–1.87 (m, 2H),
1.83–1.53 (m, 6H). MS (EI) m/z: (M+, 337).
(S)‐3‐[4‐(Cyclopentylbuta‐1,3‐diyn‐1‐yl)phenyl]‐N‐hydroxy‐2‐oxoox-
azolidine‐5‐carboxamide (DD‐13)
Compound DD‐13 was prepared from intermediate B‐15 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.22 (s, 1H), 9.27 (s, 1H), 7.91–7.50 (m, 4H), 5.20–4.81
(m, 1H), 4.35–4.22 (m, 1H), 4.11–3.97 (m, 1H), 2.86 (q, J = 7.3, 6.7 Hz,
1H), 2.02–1.89 (m, 2H), 1.73–1.57 (m, 6H). MS (ESI) m/z: [(M–H)–,
337.0]. HRMS (ESI): Anal. calc. for C19H19O4N2: 339.1339, found:
339.1343.
Methyl (S)‐3‐{4‐[(4‐aminophenyl)buta‐1,3‐diyn‐1‐yl]phenyl}‐2‐
oxooxazolidine‐5‐carboxylate (B‐13)
Intermediate B‐13 was prepared from intermediate B‐07 and 4‐
ethynylaniline in the same manner as described for intermediate B‐
12. 1H NMR (400 MHz, chloroform‐d) δ 7.54 (s, 4H), 7.35 (d,
J = 8.3 Hz, 2H), 6.62 (d, J = 8.2 Hz, 2H), 5.11 (dd, J = 9.7, 5.2 Hz, 1H),
4.32 (t, J = 9.5 Hz, 1H), 4.17 (dd, J = 9.5, 5.8 Hz, 1H), 3.90 (s, 3H). MS
(ESI) m/z: [(M+H)+, 361.2].
Methyl (S)‐3‐{4‐[(1‐hydroxycyclopentyl)buta‐1,3‐diyn‐1‐yl]phenyl}‐2‐
oxooxazolidine‐5‐carboxylate (B‐16)
(S)‐3‐{4‐[(4‐Aminophenyl)buta‐1,3‐diyn‐1‐yl]phenyl}‐N‐hydroxy‐2‐
oxooxazolidine‐5‐carboxamide (DD‐10)
Intermediate B‐16 was prepared from intermediate B‐07 and 1‐
ethynylcyclopentanol in the same manner as described for inter-
mediate B‐12. 1H NMR (400 MHz, chloroform‐d) δ 7.49 (s, 4H), 5.08
(dd, J = 9.6, 5.2 Hz, 1H), 4.29 (t, J = 9.5 Hz, 1H), 4.13 (dd, J = 9.3,
5.3 Hz, 1H), 3.87 (s, 3H), 2.07–1.93 (m, 5H), 1.89–1.81 (m, 2H),
1.80–1.73 (m, 2H). MS (ESI) m/z: [(M+H)+, 353.1].
Compound DD‐10 was prepared from intermediate B‐13 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.22 (s, 1H), 9.28 (s, 1H), 7.75–7.52 (m, 4H), 7.24 (d,
J = 8.2 Hz, 2H), 6.54 (d, J = 8.1 Hz, 2H), 5.81 (s, 2H), 4.99 (dd, J = 9.0,
5.2 Hz, 1H), 4.29 (t, J = 9.4 Hz, 1H), 4.04 (dd, J = 8.9, 5.3 Hz, 1H). 13C
NMR (126 MHz, DMSO‐d6) δ 164.84, 153.84, 151.10, 139.18, 134.31
(overlap), 133.43 (overlap), 118.28 (overlap), 116.37, 114.04 (over-
lap), 105.99, 84.84, 81.01, 74.88, 71.78, 69.50, 47.60. MS (ESI) m/z:
[(M–H)–, 359.9]. HRMS (ESI): Anal. calc. for C20H14O4N3: 360.0990,
found: 360.0991.
(S)‐N‐Hydroxy‐3‐{4‐[(1‐hydroxycyclopentyl)buta‐1,3‐diyn‐1‐yl]phe-
nyl}‐2‐oxooxazolidine‐5‐carboxamide (DD‐14)
Compound DD‐14 was prepared from intermediate B‐16 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.23 (s, 1H), 9.29 (s, 1H), 7.61 (q, J = 8.5 Hz, 4H), 5.52 (s,

DING ET AL.
11 of 13
|
1H), 5.00 (dd, J = 9.2, 5.4 Hz, 1H), 4.29 (t, J = 9.3 Hz, 1H), 4.05 (dd,
J = 9.1, 5.4 Hz, 1H), 1.98–1.82 (m, 4H), 1.76–1.54 (m, 4H). 13C NMR
(126 MHz, DMSO‐d6) δ 164.82, 153.83, 139.46, 133.69 (overlap),
118.24 (overlap), 115.77, 89.13, 78.39, 73.72, 73.37, 69.50, 66.70,
47.58, 42.26, 23.50. MS (ESI) m/z: [(M–H)–, 352.9]. HRMS (ESI): Anal.
calc. for C19H19O5N2: 355.1288, found: 355.1279.
6.8 mmol) were added. The resulting solution was stirred for 1 hr at
room temperature and monitored by TLC. The posttreatment
process was the same as Step (a) in method A to give 0.86 g (86%)
of C‐03 as a white solid. 1H NMR (400 MHz, chloroform‐d) δ 7.55 (d,
J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H), 4.12 (t, J = 6.8 Hz, 2H), 2.87 (t,
J = 6.8 Hz, 2H), 2.21 (s, 3H). MS (ESI) m/z: [(M+H)+, 295.0].
Methyl (S)‐3‐[4‐(5‐methylhexa‐1,3‐diyn‐1‐yl)phenyl]‐2‐oxooxazoli-
dine‐5‐carboxylate (B‐17)
1‐Iodo‐4‐[2‐(methylsulfonyl)ethoxy]benzene (C‐05)
Step (b). Intermediate C‐03 (0.50 g, 1.7 mmol) was dissolved in the
dry DCM (15 ml) at room temperature, then mCPBA (0.62 g,
3.6 mmol) was added. The resulting solution was stirred for 2 hr at
room temperature and monitored by TLC. Saturated sodium
bisulfite solution was added, and it was extracted with EtOAc.
The organic phase was washed with saturated NH4Cl solution and
brine, dried over anhydrous Na2SO4, and filtered, and then the
filtrate was concentrated in vacuo. The residue was purified by
chromatography to give 0.50 g (90%) of C‐05 as a white solid. 1H
NMR (400 MHz, chloroform‐d) δ 7.60 (d, J = 9.0 Hz, 2H), 6.69 (d,
J = 9.0 Hz, 2H), 4.41 (t, 2H), 3.44 (t, J = 5.3 Hz, 2H), 3.05 (s, 3H). MS
(ESI) m/z: [(M+H)+, 327.0].
Intermediate B‐17 was prepared from intermediate B‐07 and 3‐
methyl‐1‐butyne in the same manner as described for intermediate
B‐12. 1H NMR (400 MHz, chloroform‐d) δ 7.51 (s, 4 H), 5.10 (dd,
J = 9.7, 5.3 Hz, 1H), 4.32 (t, J = 9.5 Hz, 1H), 4.21–4.12 (m, 1H), 3.90 (s,
3H), 2.74 (p, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H). MS (ESI) m/z: (M+,
311).
(S)‐N‐Hydroxy‐3‐[4‐(5‐methylhexa‐1,3‐diyn‐1‐yl)phenyl]‐2‐oxooxa-
zolidine‐5‐carboxamide (DD‐15)
Compound DD‐15 was prepared from intermediate B‐17 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.18 (s, 1H), 9.54–9.18 (m, 1H), 7.80–7.14 (m, 4H), 4.97
(dd, J = 9.2, 5.4 Hz, 1H), 4.26 (t, J = 9.3 Hz, 1H), 4.01 (dd, J = 9.2,
5.4 Hz, 1H), 2.77 (p, J = 6.8 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H). MS (ESI)
m/z: (M+, 312). HRMS (ESI): Anal. calc. for C17H17O4N2: 313.1183,
found: 313.1189.
(S)‐3‐[4‐({4‐[2‐(Methylsulfonyl)ethoxy]phenyl}ethynyl)phenyl]‐2‐
oxooxazolidine‐5‐carboxylate (C‐07)
Step (c). Intermediate C‐07 was prepared from intermediate C‐05
and B‐05 in the same manner as described for intermediate B‐09 in
method A. 1H NMR (400 MHz, chloroform‐d) δ 7.53 (s, 4H), 7.49 (d,
J = 9.0 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.09 (dd, J = 9.6, 5.3 Hz, 1H),
4.49–4.45 (m, 2H), 4.32 (t, J = 9.5 Hz, 1H), 4.17 (dd, J = 9.3, 5.3 Hz,
1H), 3.89 (s, 3H), 3.51–3.39 (m, 2H), 3.08 (s, 3H). MS (ESI) m/z:
[(M+H)+, 445.0].
Methyl (S)‐3‐[4‐(5‐hydroxy‐5‐methylhexa‐1,3‐diyn‐1‐yl)phenyl]‐2‐
oxooxazolidine‐5‐carboxylate (B‐18)
Intermediate B‐18 was prepared from intermediate B‐07 and 3‐
methyl butynol in the same manner as described for intermediate B‐
12. 1H NMR (400 MHz, chloroform‐d) δ 7.50 (s, 4H), 5.09 (dd, J = 9.6,
5.2 Hz, 1H), 4.30 (t, J = 9.5 Hz, 1H), 4.14 (dd, J = 9.3, 5.3 Hz, 1H), 3.87
(s, 3H), 2.08 (s, 1H), 1.58 (s, 6H). MS (ESI) m/z: [(M+H)+, 327.1].
(S)‐N‐Hydroxy‐3‐[4‐({4‐[2‐(methylsulfonyl)ethoxy]phenyl}ethynyl)‐
phenyl]‐2‐oxooxazolidine‐5‐carboxamide (DD‐6)
(S)‐N‐Hydroxy‐3‐[4‐(5‐hydroxy‐5‐methylhexa‐1,3‐diyn‐1‐yl)phenyl]‐
2‐oxooxazolidine‐5‐carboxamide (DD‐16)
Step (d). Compound DD‐6 was prepared from intermediate C‐07 in
the same manner as described for compound DD‐2. 1H NMR
(400 MHz, DMSO‐d6) δ 8.88 (s, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.56 (d,
J = 8.7 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 5.01
(dd, J = 9.3, 5.5 Hz, 1H), 4.39 (t, J = 5.6 Hz, 2H), 4.30 (t, J = 9.1 Hz, 1H),
4.04 (dd, J = 9.2, 5.5 Hz, 1H), 3.65 (t, J = 5.7 Hz, 2H), 3.09 (s, 3H). 13C
NMR (126 MHz, DMSO‐d6) δ 164.84, 158.31, 153.91, 138.46, 133.41
(overlap), 132.43 (overlap), 118.25 (overlap), 117.94, 115.52, 115.43
(overlap), 89.41, 88.39, 69.45, 62.52, 53.74, 47.63, 42.77. MS (ESI)
m/z: [(M–H)–, 442.8]. HRMS (ESI): Anal. calc. for C21H21O7N2S:
445.1064, found: 445.1075.
Compound DD‐16 was prepared from intermediate B‐18 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.23 (s, 1H), 9.29 (s, 1H), 7.61 (q, J = 8.5 Hz, 4H), 5.67 (s,
1H), 5.00 (dd, J = 9.3, 5.5 Hz, 1H), 4.29 (t, J = 9.3 Hz, 1H), 4.04 (dd,
J = 9.2, 5.5 Hz, 1H), 1.43 (s, 6H). 13C NMR (126 MHz, DMSO‐d6) δ
164.82, 153.84, 139.50, 133.71 (overlap), 118.25 (overlap), 115.70,
90.01, 78.30, 73.57, 69.50, 65.75, 64.31, 47.58, 31.52 (overlap). MS
(ESI) m/z: [(M–H)–, 328.1]. HRMS (ESI): Anal. calc. for C17H15O5N2:
327.0981, found: 327.0987.
|
4.1.4
Compounds synthesized by Method C
[3‐(4‐Iodophenoxy)propyl](methyl)sulfane (C‐04)
(Scheme 3)
Intermediate C‐04 was prepared from intermediate C‐02 in the same
manner as described for intermediate C‐03. 1H NMR (400 MHz,
chloroform‐d) δ 7.60–7.52 (m, 2H), 6.72–6.67 (m, 2H), 4.05 (t,
J = 6.1 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.14 (s, 3 H), 2.12–2.04 (m, 2H).
MS (ESI) m/z: [(M+H)+, 309.0].
[2‐(4‐Iodophenoxy)ethyl](methyl)sulfane (C‐03)
Step (a). Intermediate C‐01 (0.31 g, 3.4 mmol) was dissolved in the
dry THF (6.0 ml) under argon protection at room temperature, then
4‐iodophenol (0.82 g, 3.7 mmol), DIAD (1.0 g, 5.1 mmol), PPh3 (1.8 g,

12 of 13
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1‐Iodo‐4‐[3‐(methylsulfonyl)propoxy]benzene (C‐06)
4‐Ethynyl‐N‐methylbenzenesulfonamide (D‐04)
Intermediate C‐06 was prepared from intermediate C‐04 in the same
manner as described for intermediate C‐05. 1H NMR (400 MHz,
chloroform‐d) δ 7.56 (d, J = 9.1 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 4.08 (t,
J = 5.8 Hz, 2H), 3.28–3.18 (m, 2H), 2.95 (s, 3H), 2.40–2.28 (m, 2H). MS
(ESI) m/z: [(M+H)+, 441.0].
Step (c). Intermediate D‐03 (0.90 g, 3.4 mmol) was dissolved in
the dry MeOH (10 ml), then K2CO3 (0.70 g, 5.1 mmol) was added
under argon protection at room temperature. The resulting
solution was stirred for 2 hr and monitored by TLC. The
posttreatment process was the same as Step (a) in method A to
give 0.59 g (90%) of D‐04 as a yellow solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.87–7.79 (m, 2H), 7.67–7.56 (m, 2H), 4.47 (d,
J = 5.4 Hz, 1H), 3.26 (d, J = 0.8 Hz, 1H), 2.67 (dd, J = 5.4, 0.8 Hz,
3H). MS (ESI) m/z: [(M–H)–, 194.1].
Methyl (S)‐3‐[4‐({4‐[3‐(methylsulfonyl)propoxy]phenyl}ethynyl)phe-
nyl]‐2‐oxooxazolidine‐5‐carboxylate (C‐08)
Intermediate C‐08 was prepared from intermediate C‐06 and B‐05 in
the same manner as described for intermediate B‐09 in method A. 1H
NMR (400 MHz, DMSO‐d6) δ 7.96–7.78 (m, 4H), 7.72–7.59 (m, 5H),
5.37 (dd, J = 9.8, 5.1 Hz, 1H), 4.42 (t, J = 9.6 Hz, 1H), 4.22 (dd, J = 9.3,
5.1 Hz, 1H), 3.77 (s, 3H), 2.44 (d, J = 5.0 Hz, 3H). MS (ESI) m/z:
[(M–H)–, 437.0].
Methyl (S)‐3‐(4‐{[4‐(N‐methylsulfamoyl)phenyl]ethynyl}phenyl)‐2‐
oxooxazolidine‐5‐carboxylate (D‐05)
Step (d). Intermediate D‐05 was prepared from intermediate D‐04
and B‐05 in the same manner as described for intermediate B‐09 in
method A. 1H NMR (400 MHz, chloroform‐d) δ 7.83 (d, J = 8.7 Hz,
2H), 7.65 (d, J = 8.7 Hz, 2H), 7.57 (s, 4H), 5.11 (dd, J = 9.6, 5.2 Hz, 1H),
4.39–4.29 (m, 2H), 4.18 (dd, J = 9.3, 5.3 Hz, 1H), 3.89 (s, 3H), 2.69 (d,
J = 5.4 Hz, 3H). MS (ESI) m/z: [(M–H)–, 413.0].
(S)‐N‐Hydroxy‐3‐[4‐({4‐[3‐(methylsulfonyl)propoxy]phenyl}ethynyl)‐
phenyl]‐2‐oxooxazolidine‐5‐carboxamide (DD‐7)
Compound DD‐7 was prepared from intermediate C‐08 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.24 (s, 1H), 9.30 (s, 1H), 7.82 (s, 4H), 7.68 (s, 4H), 7.63
(d, J = 5.1 Hz, 1H), 5.05–4.96 (m, 1H), 4.31 (t, J = 9.4 Hz, 1H),
4.11–4.00 (m, 1H), 2.44 (d, J = 5.1 Hz, 3H). 13C NMR (126 MHz,
DMSO‐d6) δ 164.80, 153.84, 140.43, 139.98, 133.98 (overlap),
133.58 (overlap), 127.52 (overlap), 125.00, 118.29 (overlap),
115.05, 83.67, 80.67, 76.59, 73.35, 69.53, 47.59, 29.09. MS (ESI)
m/z: [(M–H)–, 437.8]. HRMS (ESI): Anal. calc. for C21H16O6N3S:
438.0760, found: 438.0756.
(S)‐N‐Hydroxy‐3‐(4‐{[4‐(N‐methylsulfamoyl)phenyl]ethynyl}phenyl)‐
2‐oxooxazolidine‐5‐carboxamide (DD‐8)
Step (f). Compound DD‐8 was prepared from intermediate D‐05 in
the same manner as described for compound DD‐2. 1H NMR
(400 MHz, DMSO‐d6) δ 9.29 (s, 1H), 7.85–7.75 (m, 4H), 7.72–7.62
(m, 4H), 7.58 (q, J = 5.1 Hz, 1H), 5.01 (dd, J = 9.3, 5.4 Hz, 1H), 4.31 (t,
J = 9.2 Hz, 1H), 4.06 (dd, J = 9.2, 5.4 Hz, 1H), 2.44 (d, J = 4.3 Hz, 3H).
13C NMR (126 MHz, DMSO‐d6) δ 164.81, 153.89, 139.29, 139.21,
132.91 (overlap), 132.41 (overlap), 127.50 (overlap), 126.85, 118.27
(overlap), 116.82, 92.43, 88.25, 69.51, 47.61, 29.12. MS (ESI) m/z:
[(M–H)–, 413.8]. HRMS (ESI): Anal. calc. for C19H18O6N3S: 416.0911,
found: 416.0904.
|
4.1.5
Compounds synthesized by Method D
(Scheme 4)
4‐Bromo‐N‐methylbenzenesulfonamide (D‐02)
Step (a). 4‐Bromobenzenesulfonyl chloride (0.51 g, 2.0 mmol) was
dissolved in the dry THF (15 ml) at 0℃, then methylamine
(dissolved in ethanol, 5.0 ml) was added. The resulting solution
was stirred for 4 hr at 0℃ and monitored by TLC. The posttreat-
ment process was the same as Step (a) in method A. The
concentrated product was used in the next step without any
further purification. MS (EI) m/z: (M+, 249).
(S)‐3‐(4‐{[4‐(N‐Methylsulfamoyl)phenyl]buta‐1,3‐diyn‐1‐yl}phenyl)‐2‐
oxooxazolidine‐5‐carboxylate (D‐06)
Step (e). Intermediate D‐06 was prepared from intermediate B‐04
and B‐07 in the same manner as described for intermediate B‐12. 1
H
NMR (400 MHz, DMSO‐d6) δ 7.96–7.78 (m, 4H), 7.72–7.59 (m, 5H),
5.37 (dd, J = 9.8, 5.1 Hz, 1H), 4.42 (t, J = 9.6 Hz, 1H), 4.22 (dd, J = 9.3,
5.1 Hz, 1H), 3.77 (s, 3H), 2.44 (d, J = 5.0 Hz, 3H). MS (ESI) m/z:
[(M–H)–, 437.0].
N‐Methyl‐4‐[(trimethylsilyl)ethynyl]benzenesulfonamide (D‐03)
Step (b). Intermediate D‐02 (1.1 g, 4.5 mmol) was dissolved in the dry
THF (10 ml), then DIEA (2.3 g, 18 mmol), Pd(PPh3)2Cl2 (95 mg,
0.14 mmol), CuI (26 mg, 0.14 mmol), trimethylsilylacetylene (0.53 g,
5.4 mmol) were added under argon protection at room temperature.
The resulting solution was stirred for 12 hr at 80℃ and monitored by
TLC. The posttreatment process was the same as Step (a) in method
A to give 0.90 g (75.0%) of D‐03 as a yellow solid. 1H NMR (400 MHz,
chloroform‐d) δ 7.85–7.73 (m, 2H), 7.63–7.55 (m, 2H), 4.37 (t,
J = 5.4 Hz, 1H), 2.66 (d, J = 5.4 Hz, 3H), 0.26 (s, 9H). MS (ESI) m/z:
[(M–H)–, 266.0].
(S)‐N‐Hydroxy‐3‐(4‐{[4‐(N‐methylsulfamoyl)phenyl]buta‐1,3‐diyn‐1‐
yl}phenyl)‐2‐oxooxazolidine‐5‐carboxamide (DD‐11)
Compound DD‐11 was prepared from intermediate D‐06 in the same
manner as described for compound DD‐2. 1H NMR (400 MHz,
DMSO‐d6) δ 11.24 (s, 1H), 9.30 (s, 1H), 7.82 (s, 4H), 7.68 (s, 4H), 7.63
(d, J = 5.1 Hz, 1H), 5.05–4.96 (m, 1H), 4.31 (t, J = 9.4 Hz, 1H),
4.11–4.00 (m, 1H), 2.44 (d, J = 5.1 Hz, 3H). 13C NMR (126 MHz,
DMSO‐d6) δ 164.80, 153.84, 140.43, 139.98, 133.98 (overlap),
133.58 (overlap), 127.52 (overlap), 125.00, 118.29 (overlap),
115.05, 83.67, 80.67, 76.59, 73.35, 69.53, 47.59, 29.09. MS(ESI)

DING ET AL.
13 of 13
|
m/z: [(M–H)–, 437.8]. HRMS (ESI): Anal. calc. for C21H16O6N3S:
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4.2
Biochemical pharmacology
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4.2.1
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|
4.2.2
Liver microsomal stability assay
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(5.0 mM), tested compound (final concentration 0.10 μM, 0.01%
DMSO, 0.005% bovine serum albumin). Then NADPH (1.0 mM) was
added at 37℃ and incubated for 60 min. The reaction can be started
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SUPPORTING INFORMATION
Additional supporting information may be found online in the
Supporting Information section.
ACKNOWLEDGMENT
This work was supported by grants from the Youth Project of
Education Department of Liaoning Province (No. LQN201709) and
National Natural Science Foundation of China (No. 21807055).
How to cite this article: Ding S, Ji J‐C, Zhang M‐J, et al.
Exploration of the structure–activity relationship and
druggability of novel oxazolidinone‐based compounds as
Gram‐negative antibacterial agents. Arch Pharm Chem Life Sci.
2019;e1900129. https://doi.org/10.1002/ardp.201900129
ORCID
Ju Liu
http://orcid.org/0000-0003-1415-1099