Design, Synthesis, and Cytotoxic Activity of 3-Aryl-N-hydroxy-2-(sulfonamido)propanamides in HepG2, HT-1080, KB, and MCF-7 Cells

Article abstract of DOI:10.1002/cbdv.201800646

A new series of (sulfonamido)propanamides (6a1–6a13, 6b1–6b15, 7c1–7c5, 6d1–6d5, 6e1–6e6) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their in vitro c

Full text of DOI:10.1002/cbdv.201800646

Title: Design, synthesis, and cytotoxic activity of 3-aryl-N-
hydroxy-2(sulfonamido)propanamides in HepG2, HT-1080, KB,
and MCF-7 cells
Authors: duan yang shao, Guo-Ning Zhang, Weixiao Niu, Mei Zhu,
Juxian Wang, Donghui Li, Yucheng Wang, and Zi-qiang Li
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201800646
Link to VoR: http://dx.doi.org/10.1002/cbdv.201800646

Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Design, synthesis, and cytotoxic activity of 3-aryl-N-hydroxy-
2(sulfonamido)propanamides in HepG2, HT-1080, KB, and MCF-7 cells
a
b
b
b
b
b
Duanyang Shao , Guo-Ning Zhang , Weixiao Niu , Ziqiang Li , Mei Zhu , Juxian Wang , Donghui
a*
b*
Li , Yucheng Wang
a
School of Pharmacy, Jinzhou Medical University, Jinzhou 121001, P. R. China;
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China；
Corresponding authors: lidonghuilx@sina.com (D. H. Li); wangyucheng@imb.pumc.edu.cn (Y. C. Wang)
b
*
Abstract: A new series of compounds containing (sulfonamido) propanamide (6a1-13, 6b1-15, 7c1-5, 6d1-5, 6e1-6) was designed and
synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated
for their in vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT-1080), mouth epidermal carcinoma (KB),
and breast adenocarcinoma (MCF-7) cells with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls.
Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most
potent compound, 6a7, shows the IC50 values of 29.78 ± 0.516 μM, 30.70 ± 0.61 μM, and 64.89 ± 3.09 μM in HepG2, HT-1080, KB, and MCF-
7
cells, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.
Keywords: Sulfonamido; Cytotoxic; Synthesis; SRB Assay.
Introduction
Cancer is a major illness that seriously endangers human life and health.[1 - 3] In recent years, cancers have been responsible for 8.2 million
human deaths worldwide.[4 - 5] According to the World Health Organization (WHO), tumours have been the main cause of morbidity and
mortality.[6] Cancer is one of the most serious threats against humans, and the clinical prognosis remains relatively poor.[7 - 10] Surpassing
cardiovascular diseases, cancer has taken the position as the number one killer due to various worldwide factors.[11 - 13] Cancer is a
pathological condition that occurs due to genetic factors during development, resulting in cell death via excessive proliferation and
apoptosis.[14]
Currently, there is no absolute effective treatment for cancer patients in clinical practice, but chemotherapy is still the most widely used
form of cancer treatment.[15 - 20] The FDA approved anticancer drugs can be devided into two main gropus: cytotoxic antineoplastics and
targeted antineoplastics. The cytotoxic antibiotics are a varied group of drugs having various mechanisms of action which contains
alkylating agents, antimicrotubule agents, topoisomerase inhibitors and antimetabolites; while most of the targeted antineoplastics belong
to signal transduction inhibitors, gene expression modulators, apoptosis induces, hormone therapies, and monoclonal antibodies.[21] There
are many successful anticancer drugs such as: vincristine, paclitaxel and its derivates docetaxel and cabazitaxel, irinotecan, topotecan,
carboplatin, cisplatin and imatinib in the history of anticancer drugs development. However, the majority of cancers are either resistant to
chemotherapy, or they acquire resistance during treatment.[22 - 25] Thus, studies involving the synthesis of new compounds and the
investigation of their bioactive potential represent an important goal for the development of new cancer drugs.[26 - 30]
Herein, we communicate the synthesis, biological data and structure - activity relationship (SAR) of a series of novel 3-aryl-N-hydroxy-2-
(sulfonamido)propanamide based cytotoxic reagents. In the present study, 2-(sulfonamido) propanamide was used as the parent compound
for the design of new anticancer compounds. In total, 44 novel 3-aryl-N-hydroxy-2-(sulfonamido)propenamide compounds were designed
1
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Chemistry & Biodiversity
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Chem. Biodiversity
and synthesized by the sulfonyl esterification of naphthylpropionamide (D/L), phenylpropionamide (D/L), and hydroxypropionamide (D)
with different sulfonyl chlorides in an alkaline medium, followed by amination via aqueous hydroxylamine solution.
Results and Discussion
Chemistry
Compounds 6a - b, d - e, and 7c (Tables 1 - 4) with diferent aromantic group substitutions and chiral centers were designed to expore their
cytotoxic effect. The target compounds were obtained through the route depicted in Scheme 1. The synthesis of novel derivatives was
completed using 3-(2-Naphthyl)-D-alanine (a), 3 - (2 - naphthyl) - L - alanine (b), 4 - bromo - L - phenylalanine (c), 4 - bromo - D -
phenylalanine (d) and D - tyrosine ethyl ester hydrochloride (e) as key starting materials. The conversion of the starting materials (1a - e) to
the corresponding esters (2a - b, d - e, and 3c) was conducted in the presence of SOCl2 and methanol. Then, the intermediates 4(a - b, d -
e) and 5c were synthesized by the sulfonylation of 2a - b, d - e, and 3c with different sulfonyl chlorides in the presence of DIPEA.
Subsequently, aminolysis of the ester moiety with aqueous hydroxylamine (50 percent w/w) led to the target hydroxamic acid (6a - b, d - e,
7
c).
Table 1. The structures of the compounds 6a1 - 6a13
O
(
R)
OH
N
H
NH
O
S
R
O
Compound (D)
R
Compound (D)
R
S
F
F
Br
6
6
6
6
6
a
a
a
1
2
3
6a
8
F
O
6a
9
N
H
N
6a10
6a11
6a12
HO
O
NO2
a
4
N
a
5
NO2
6
a
6
6a13
NO
2
6
a
7
Table 2. The structures of the compounds 6b1 - 6b15
2
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O
(
S)
OH
N
H
NH
Br
O
S
R
O
Compound (L)
R
Compound (L)
6b9
R
O
F
F
6
6
b1
b2
N
F
H
6b10
6b11
6b12
6b13
2
H N
NO2
6
b3
O
6
b4
b5
N
NO2
6
NO
2
6
b6
6b14
6b15
6
b7
Br
S
6
b8
Br
Table 3. The structures of the compounds 6d1 - 6d5, 6e1 - 6e6
O
O
(
R)
OH
(S)
OH
N
N
H
H
NH
NH
Br
O
O
S
S
R
O
R
O
Compound (D)
R
Compound (L)
6e1
R
6d1
6d2
6d3
6d4
6d5
6e2
6e3
6e4
6e5
Br
Br
F
F
F
F
F
F
NO2
O
NO2
6
e6
3
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Table 4. The structures of the compounds 7c1 - 7c5
O
(
R)
OH
N
H
NH
S
O
HO
O
R
Compound(D)
R
Compound (D)
R
7
c1
7c4
7c5
Br
7
7
c2
c3
O
F
F
F
O
O
Ar
OH
a) SOCl2
MeOH
Ar
O
NH2
NH2
O
b) DIPEA
DCM
2a-b,d-e
1a-b,d-e
Cl
S
R
O
O
O
NH2
HO
3c
O
O
OH
Ar
O
Ar
N
H
NH
NH
O
O
O
O
S
S
R
R
6a-b,d-e
c) aqueous hydroxylamine(55%)
MeOH
4a-d,d-e
O
O
OH
N
O
H
NH
S
O
NH
HO
HO
O
S
O
R
R
O
5c
7c
Scheme 1. Synthesis of compounds 6a1 - a13, 6b1 - b15, 6d1 - d5, 6e1 - e5, 7c1 - c5. Reagents and conditions: a) MeOH, SOCl2, 0 °C, 4 h;. b) CH2Cl2,
DIPEA, rt, 6 h; c) MeOH, aqueous hydroxylamine(55%), rt, 12 h.
Biological evaluation
1
.
SRB assay
The cytotoxicities of the tested compounds against the human cancer cell lines HepG2 (hepatocellular carcinoma), MCF-7 (breast
adenocarcinoma), KB (mouth epidermal carcinoma) and HT-1080 (fibrosarcoma) were evaluated by the sulforhodamine B (SRB) assay using
4
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Chem. Biodiversity
a standard protocol developed by the NCI (National Cancer Institute). HepG2, HT-1080 and MCF-7 cells were maintained in Dulbecco’s
modified Eagle’s medium (DMEM, HyClone), and KB cells were maintained in RPMI 1640 medium (HyClone.) All media contained 100
units/mL of penicillin, 100ꢀmg/mL of streptomycin and 10% foetal bovine serum. For the cytotoxicity assays, the cells were inoculated in 96
-
well plates at a concentration of 4000 cells per well. After incubation at 37ꢀ°C under a humidified atmosphere containing 5% CO2 for 24ꢀh,
the cells were treated with various concentrations of the test compounds in triplicate and were further incubated for 48ꢀh. Cell proliferation
was determined by the SRB assay. The IC50 value was defined as the compound concentration that produces 50% inhibition of cell growth
during 2 days of treatment. IC50 values were calculated using SigmaPlot 10.0 software with nonlinear regression fit analysis.
2.
In vitro cytotoxic activity against the cancer cell lines HepG2, HT1080, KB, MCF-7
The cytotoxic activities of the target compounds were evaluated in parallel against four humancancer cell lines (HepG2, HT1080, KB, and
MCF-7) by sulforhodamine B (SRB) assay. Gemcitabine and mitomycin C were used as the reference compounds. The results are
summarized in Tables 5 - 7, and values represent the average of at least three independent measurements. Most of the compounds showed
higher inhibitory activity than the compounds in the positive control group, except for the compounds 7c1 - 7c5, each of which bears a 3’ -
hydroxyphenyl group. These compounds almost had no inhibitory activity against any test cell lines. The results suggest that the hydroxyl
group on position 3 of the phenyl ring reduces the cytotoxic properties. Most compounds had a good effect on the proliferation of the cell
lines HepG2, HT1080, and KB but had no sensitivity to the cell line MCF-7.
As shown in Tables 5 - 6, most of the compounds showed higher inhibitory activity than those in the positive control group on the four cell
lines. Among these compounds, 6a1, 6a6, 6a7, 6b1, 6b5, 6b6, 6b8, 6d2, 6e1, and 6e2 showed good inhibition for cancer cell proliferation.
Compound 6a7 represented the best cytotoxic activity against HepG2, HT1080 and KB cell lines, with IC50 values of 30.18 ± 0.069 μM, 29.78
±
0.52 μM, and 30.70 ± 0.61 μM, respectively. Moreover, the different substituent groups had a significant impact on cytotoxic activity.
Compounds 6a11 - 13, each of which bears a nitryl group on the benzosulfonyl moiety, were not active in the HT1080, KB, and MCF-7 cell
lines, and compounds 6a9 - 10 also showed limited inhibition in the SRB assay. The result clearly indicates that a phenyl, alkyl,
trifluoromethyl group or bromine atom substitution on the benzenesulfonyl ring is favourable, while an electron withdrawing nitryl group
on different positions of benzenesulfonyl ring is unfavourable for its cytotoxic activity in the 4 tested cell lines. The activities of compounds
6
6
b3 and 6b9 - 13 also revealed that hydrogen-bonding substituents reduce the inhibition of cell proliferation. Each of compounds 6a1 and
b1 bears an electron withdrawing trifluoromethyl group instead of an electrion donating naphthyl group and showed better activity than
compounds 6a2 and 6b2.In addition, the preliminary structure activity relationship also revealed that the stereo-configuration had little
effect on the cytotoxic activity. There was no significant difference between the effect of the D - and L - configurations (6a1 - 3 vs 6e3 - 5,
6
b1 - 2 vs 6d3 - 4 and 6b12 vs 6d5).
Table 5. The IC50 values of the target compounds 6a1 - 6a13
IC50[μM]
Compound
HepG2
HT1080
KB
MCF-7
5
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6a1
6a2
6a3
6a4
6a5
6a6
6a7
6a8
6a9
36.29±2.17
54.69±3.5
64.91±0.09
72.74±0.26
>100
42.19±11.53
55.37±1.24
62.21±6.11
81.34±2.72
>100
35.41±0.18
63.60±14.72
98.15±2.31
82.81±1.13
>100
69.72±15.49
>100
>100
>100
63.87±17.33
64.88±3.08
>100
31.74±1.78
30.17±0.06
44.79±13.04
>100
35.59±2.84
29.78±0.516
40.17±6.88
>100
32.80±0.10
30.69±0.60
35.70±0.48
>100
>100
>100
6
6
6
6
a10
a11
a12
a13
58.51±5.62
74.34±72.12
65.55±30.4
39.94±1.06
87.49±4.5
66.22±1.73
69.73±22.36
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
GEM
MMC
69.22±0.23
4.75±0.28
34.66±0.19
59.33±6.47
>100
25.71±1.16
Table 6. The IC50 values of the target compounds 6b1 - 4b15
IC50 [μM]
Compound
HepG2
33.70±0.44
57.95±13.18
>100
HT1080
31.86±1.11
>100
KB
MCF-7
6b1
6b2
6b3
6b4
6b5
>100
80.49±3.83
>100
>100
>100
> 100
>100
56.01±7.95
32.51±0.20
31.02±0.35
>100
45.33±0.18
35.31±3.06
33.77±1.74
>100
39.70±7.3
33.59±0.23
34.49±2.57
>100
51.23±19.22
83.97±5.26
65.74±4.45
>100
6
b6
b7
6
6
6
b8
b9
40.20±4.19
>100
46.69±9.06
>100
33.40±0.46
>100
>100
>100
6
6
6
6
6
6
b10
b11
b12
b13
b14
b15
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
52.98±12.19
43.75±12.62
87.49±4.5
66.22±1.73
51.3±2.32
54.05±5.25
69.22±0.23
4.75±0.28
39.23±4.97
41.23±9.55
34.66±0.19
59.33±6.47
86.76±2.58
88.45±3.23
>100
GEM
MMC
25.71±1.16
Table 7. The IC50 values of the target compounds 7c1 - 4c5, 6d1 - 4d5, 6e1 - 4e6
IC50 [μM]
Compound
HepG2
HT1080
KB
MCF-7
6
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7c1
7c2
7c3
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
7
c4
c5
>100
>100
>100
>100
7
>100
>100
>100
>100
6d1
6d2
6d3
6d4
6d5
52.01±11.48
37.06±1.96
>100
>100
40.87±5.23
35.69±0.28
>100
46.35±12.09
84.30±0.71
>100
31.96±0.25
>100
>100
>100
>100
>100
>100
>100
>100
>100
6e1
6e2
6e3
6e4
6e5
6e6
34.52±0.26
37.25±5.45
60.99±9.22
44.65±2.74
71.17±11.42
>100
46.84±14
33.85±2.64
59.84±3.89
46.14±8.85
>100
38.56±0.37
35.75±0.31
65.48±15.72
57.14±13.10
>100
55.45±20.29
74.51±17.45
86.74±5.63
>100
>100
>100
>100
>100
GEM
MMC
87.49±4.5
66.22±1.73
69.22±0.23
4.75±0.28
34.66±0.19
59.33±6.47
>100
25.71±1.16
Conclusions
In this paper, we designed and synthesized a series of sulfonyl - propionamide derivatives containing a total of 44 compounds. The structures
of these compounds were confirmed by 1HNMR, 13CNMR and ESI - MS, and their cytotoxic effect were evaluated with the SRB assay. Most
compounds showed moderate to excellent inhibitory effects on cell proliferation, and compounds 6a1, 6a6, 6a7, 6a13, 6b1, 6b5, 6b6, 6b8,
6
d2, 6e1, and 6e2 were identified as the most promising cytotoxic compounds.
The cytotoxic effect of these compounds was inferior to that of the leading compound mitomycin C. Analysis of the test results revealed
that the introduction of an electron donating group at the C-4 position of the sulfonyl group showed a significant decrease in the cytotoxic
effect compared to the introduction of an electron withdrawing group. A hydrogen-bonding substituent on the benzosulfonyl ring was also
unfavourable for the cytotoxic effect. The introduction of a hydroxyl group at the 3 - position of the benzene ring of propionamide increased
the cytotoxic activity of the compound. These compounds were selective for cancer cells. Most of the compounds showed higher inhibitory
activity than the positive control on three of four cell lines; compounds had a good effect on the proliferation of the cell lines HepG2, HT1080,
and KB but had no sensitivity to the cell line MCF-7 Experimental Section
Experimental Section
General information
Reagents were from Shanghai Chemical Reagent Company and used without further purification. Melting points were taken on a MP70
melting point apparatus, uncorrected and reported in degrees Centigrade. HNMR and 13CNMR spectra were recorded in DMSO on a
1
BRUKER AVANCE Ⅲ HD (600 MHz) using TMS as internal standard. Column chromatography at Teledyne Isco - Combiflash Rf 200. The
spectrum
Abbreviations used. DIPEA, N,N-diisopropylethylamine; HNMR, Nuclear magnetic resonance; min, Minute; TLC, Thin layer
chromatography; ESI - MS, Electron spray ionization mass spectrum; h, Hour ; DCM, Dichloromethane; δ(ppm), chemical shift.
Synthesis of Methyl (R)-2-amino-3-(naphthalen-2-yl) propanoate (2a)
7
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To a solution of the 3-(2-Naphthyl)-D-alanine (1g, 6.05 mmol) in the 10ml of anhydrous methanol, SOCl2 (7.14g, 60.05 mmol) was added at
°C. Then the solution was stirred at room temperature for 4 h until the completion of the reaction monitored by TLC.
0
General synthesis of compounds 4a-b,d-e and 5c
A suspension of D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol), i-Pr2NEt (1.1 mL, 6.54 mmol) and 4-(trifluoromethyl)
benzenesulfonyl chloride (0.64 g, 2.62 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The solution was washed with 10 percent
NaHCO3(20 mL), dried (NaSO4), concentrated, then chromatographed (CH2Cl2 to 1 percent MeOH/CH2Cl2) and concentrated to provide
0.6 g of the sulfonamide ester.
Synthesis of Methyl(R)-3-(naphthalene-2-yl)-2-((4-(trifluoromethyl) phenyl) sulfonamide) propanoate (4a1)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4-(trifluoromethyl) benzenesulfonyl chloride (0.64
1
g, 2.62 mmol), the target product was obtained as a white solid (0.6g) H NMR (600 MHz, Chloroform - d) δ 7.79 – 7.75 (m, 1H), 7.71 – 7.67 (m,
1
H), 7.67 – 7.62 (m, 3H), 7.50 (d, J = 1.6 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.14 – 7.10 (m, 1H), 5.47 (d, J = 9.2 Hz, 1H), 4.38 –
.12 (m, 1H), 3.60 (s, 3H), 3.29 – 3.24 (m, 1H), 3.10 – 3.05 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 171.3, 143.1, 134.0, 133.3, 132.4, 132.4, 128.4,
28.3, 127.6, 127.5, 127.4(2C), 126.9, 126.4, 126.0, 125.8, 125.7, 123.0, 57.1, 52.7, 39.3; ESI - Mass for C21H18F3NO4S: m/z [M + Na]+ : 460.3.
4
1
Synthesis of Methyl(R)-2-((4-methylphenyl) sulfonamide)-3-(naphthalene-2-yl) propanoate (4a2)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4 - methylbenzenesulfonyl chloride (0.498 g, 2.62
mmol), the target product was obtained as a white solid (0.56 g).1H NMR (600 MHz, Chloroform - d) δ 7.81 – 7.76 (m, 1H), 7.74 – 7.68 (m,
2H), 7.58 – 7.52 (m, 2H), 7.50 – 7.49 (m, 1H), 7.48 – 7.44 (m, 2H), 7.20 – 7.14 (m, 1H), 7.11 – 7.02 (m, 2H), 5.15 (d, J = 9.1 Hz, 1H), 4.47 – 4.07 (m,
1H), 3.53 (s, 3H), 3.26 – 3.20 (m, 1H), 3.16 – 3.10 (m, 1H), 2.31 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 171.4, 143.5, 136.6, 133.3, 132.6, 132.5,
+
1
29.4(2C), 128.3, 128.2, 127.6, 127.6, 127.2, 127.1(2C), 126.1, 125.8, 56.8, 52.5, 39.6, 21.5. ESI - Mass for C21H21F3NO4S: m/z [M+Na] : 406.4.
Synthesis of Methyl (R)-2-((4-methoxyphenyl) sulfonamide)-3-(naphthalene-2-yl) propanoate (4a3)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4 - methoxybenzenesulfonyl chloride (0.54 g, 2.616
mmol), the target product was obtained as a white solid (0.57 g). 1H NMR (600 MHz, Chloroform - d) δ 7.82 – 7.77 (m, 1H), 7.74 – 7.68 (m,
2H), 7.61 – 7.56 (m, 2H), 7.52 – 7.50 (m, 1H), 7.49 – 7.43 (m, 2H), 7.20 – 7.15 (m, 1H), 6.78 – 6.71 (m, 2H), 5.09 (d, J = 9.1 Hz, 1H), 4.32 – 4.23 (m,
1H), 3.77 (s, 3H), 3.55 (s, 3H), 3.26 – 3.18 (m, 1H), 3.16 – 3.08 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 171.48, 162.8, 133.3, 132.6, 132.6, 131.0,
+
1
29.2(2C), 128.3, 128.2, 127.6, 127.6, 127.2, 126.2, 125.8, 113.9(2C), 56.8, 55.6, 52.5, 39.5.ESI - Mass for C21H21F3NO5S: m/z [M+Na] : 422.3.
Synthesis of methyl (R)-3-(naphthalene-2-yl)-2-(quinolone-8-sulfonamido) propanoate (4a4)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and quinolone - 8 - sulfonyl chloride (0.6 g, 2.62 mmol),
the target product was obtained as a white solid (0.57 g). 1H NMR (600 MHz, Chloroform - d) δ 8.58 – 8.53 (m, 1H), 8.30 – 8.24 (m, 1H), 8.09
–
7.95 (m, 1H), 7.90 – 7.85 (m, 1H), 7.71 – 7.66 (m, 1H), 7.62 – 7.57 (m, 1H), 7.52 – 7.45 (m, 2H), 7.45 – 7.40 (m, 3H), 7.24 – 7.20 (m, 1H), 7.12 –
7
.00 (m, 1H), 6.84 (d, J = 7.0 Hz, 1H), 4.54 – 4.41 (m, 1H), 3.38 (s, 3H), 3.30 – 3.22 (m, 1H), 3.18 – 3.11 (m, 1H). 13C NMR (151 MHz, CDCl3) δ
8
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Chemistry & Biodiversity
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Chem. Biodiversity
171.2, 150.6, 142.7, 136.4, 136.3, 133.1, 133.0, 132.7, 132.3, 1291.0, 128.4, 128.1, 127.9, 127.7, 127.6, 126.8, 126.0, 125.7, 125.2, 121.8, 57.7, 52.1,
+
3
9.2.ESI-Mass for C23H20N2O4S: m/z [M+Na] : 443.4.
Synthesis of methyl(R)-2-((4-isopropylphenyl)sulfonamide)-3-(naphthalene-2-yl) propanoate (4a5)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4 - isopropylbenzenesulfonylchloride (0.83 g, 3.27
mmol), the target product was obtained as a white solid (0.58 g). 1H NMR (600 MHz, Chloroform - d) δ 7.81 – 7.77 (m, 1H), 7.75 – 7.69 (m,
2H), 7.62 – 7.59 (m, 2H), 7.53 (s, 1H), 7.48 – 7.44 (m, 2H), 7.20 – 7.15 (m, 3H), 5.43 – 5.05 (m, 1H), 4.45 – 4.10 (m, 1H), 3.48 (s, 3H), 3.24 – 3.20
(m, 1H), 3.18 – 3.13 (m, 1H), 2.95 – 2.84 (m, 1H), 1.59 – 0.76 (m, 6H). 13C NMR (151 MHz, CDCl3) δ 171.4, 154.3, 136.8, 133.4, 132.6, 132.5,
128.3, 128.3, 127.7, 127.6, 127.3(2C), 127.3, 1261.0(2C), 126.2, 125.9, 56.8, 52.4, 39.5, 34.1, 23.6, 23.6.ESI - Mass for C23H25F3NO4S: m/z
+
[
M+Na] : 434.4.
Synthesis of methyl(R)-2-([1, 1’-biphenyl]-4-sulfonamido)-3-(naphthalene-2-yl) propanoate (4a6)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and [1, 1’-biphenyl]-4-sulfonyl chloride (0.83 g, 3.27
mmol), the target product was obtained as a white solid (0.72 g).1H NMR (600 MHz, Chloroform - d) δ 7.77 – 7.66 (m, 6H), 7.55 – 7.50 (m, 3H),
7
.50 – 7.45 (m, 4H), 7.44 – 7.40 (m, 3H), 5.29 – 5.20 (m, 1H), 4.40 – 4.29 (m, 1H), 3.54 (s, 3H), 3.28 – 3.24 (m, 1H), 3.18 – 3.14 (m, 1H). 13C NMR
151 MHz, CDCl3) δ 171.4, 145.5, 139.1, 1371.0, 133.3, 132.5, 132.5, 1281.0(2C), 128.5, 128.3, 128.3, 127.6, 127.4, 127.6, 127.3(2C), 127.2(2C),
27.2(2C), 126.2, 125.9, 56.9, 52.5, 39.5. ESI - Mass for C26H23NO4S: m/z [M+Na]+ :468.4.
(
1
Synthesis of methyl(R)-3-(naphthalene-2-yl)-2-(naphthalene-1-sulfonamido) propanoate (4a7)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and naphthalene - 1 - chloride (0.6 g, 2.62 mmol), the
1
target product was obtained as a white solid (0.59 g). H NMR (600 MHz, Chloroform - d) δ 8.44 (d, J = 8.4 Hz, 1H), 8.18 – 8.12 (m, 1H), 7.91
(d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 6.0, 3.0 Hz, 1H), 7.57 – 7.54 (m, 1H), 7.50 – 7.35 (m, 7H), 7.30 (s, 1H), 6.99 – 6.92 (m, 1H),
5
.59 – 5.14 (m, 1H), 4.42 – 4.13 (m, 1H), 3.43 (s, 2H), 3.13 – 3.08 (m, 1H), 3.05 – 3.00 (m, 1H). 13C NMR (151 MHz, CDCl3) δ13C NMR (151 MHz,
CDCl3) δ 171.2, 134.4, 134.1, 1331.0, 133.1, 132.3, 129.5, 128.8, 128.1, 128.1(2C), 128.0, 127.9, 127.6, 127.6, 126.8, 126.7, 126.0, 125.7, 124.2,
+
1
23.8, 57.1, 52.4, 39.3.ESI - Mass for C24H21NO4S: m/z [M+Na] : 442.4.
Synthesis of methyl(R)-2-((5-bromothiophene)-2-sulfonamido-3-(naphthalene-2-yl) propanote (4a8)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 3 - bromocyclopenta - 1, 3 - diene - 1 - sulfonyl
chloride (0.685 g, 0.62 mmol), the target product was obtained as a white solid (0.62 g).1H NMR (600 MHz, DMSO-d6) δ 8.96 (d, J = 8.9 Hz,
1H), 7.88 – 7.84 (m, 1H), 7.81 – 7.74 (m, 2H), 7.65 (s, 1H), 7.51 – 7.45 (m, 2H), 7.32 – 7.29 (m, 1H), 7.10 (d, J = 4.0 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H),
4
.18 – 4.13 (m, 1H), 3.53 (s, 3H), 3.18 – 3.13 (m, 1H), 2.97 – 2.92 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.6, 143.0, 134.3, 133.3, 132.4, 132.4,
+
1
31.1, 128.3, 128.2, 1271.0, 127.9, 127.8, 126.6, 126.1, 118.7, 57.9, 52.6, 38.0.ESI - Mass for C18H16BrNO4S: m/z [M+Na] : 476.2/478.2.
Synthesis of methyl (R)-2-((4-acetamidophenyl) sulfonamido)-3-(naphthalene-2-yl)propanoate (4a9)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4 - acetamidobenzenesulfonyl chloride (0.61 g, 2.62
mmol), the target product was obtained as a white solid (0.51 g).1H NMR (600 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.85
–
7.82 (m, 1H), 7.79 – 7.73 (m, 2H), 7.59 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.51 – 7.44 (m, 4H), 7.29 – 7.24 (m, 1H), 4.12 – 4.04 (m, 1H), 3.37 (s, 3H),
9
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
3.10 – 3.06 (m, 1H), 2.95 – 2.89 (m, 1H), 2.07 (s, 3H). 13C NMR (151 MHz, DMSO) δ 171.7, 169.3, 143.1, 134.7, 134.4, 133.3, 132.4, 128.2, 128.0,
+
1
27.9, 127.8, 127.8(2C), 126.4(2C), 126.1, 118.7(2C), 57.7, 52.3, 38.3, 24.6. ESI - Mass for C22H22N2O5S: m/z [M+Na] : 449.3.
Synthesis of methyl(R)-2-((4-acetylphenyl) sulfonamido)-3-(naphthalene-2-yl) propanoate (4a10)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 4 - acetylbenzenesulfonyl chloride (0.57 g,
1
2
.62mmol), the target product was obtained as a white solid (0.54 g). H NMR (600 MHz, DMSO-d6) δ 8.79 (d, J = 9.0 Hz, 1H), 7.80 – 7.76 (m,
1H), 7.72 – 7.65 (m, 4H), 7.57 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.46 – 7.40 (m, 2H), 7.29 – 7.25 (m, 1H), 4.27 – 3.91 (m, 1H), 3.48 (s, 3H), 3.19 –
3.10 (m, 1H), 2.96 – 2.86 (m, 1H), 2.47 (s, 3H). 13C NMR (151 MHz, DMSO) δ 197.3, 171.7, 144.8, 139.1, 134.4, 133.2, 132.3, 128.7(2C), 128.2,
128.2, 127.9(2C), 127.8, 126.6(2C), 126.4, 126.1, 571.0, 52.5, 38.1, 27.3.ESI - Mass for C22H21NO5S: m/z [M + Na]+ : 434.3.
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-((3-nitrophenyl) sulfonamide) propanamide (4a11)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 3- nitrobenzenesulfonyl chloride (0.58 g, 2.62 mmol),
1
the target product was obtained as a white solid (0.52 g). H NMR (600 MHz, DMSO-d6) δ 8.96 (d, J = 8.9 Hz, 1H), 8.13 – 8.02 (m, 1H), 7.93 (d,
1H), 7.85 – 7.78 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.53 (s, 1H), 7.49 – 7.35 (m, 3H), 7.31 – 7.22 (m, 1H), 4.34 – 4.11 (m, 1H), 3.54
(s, 3H), 3.22 – 3.12 (m, 1H), 2.95 – 2.81 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.7, 147.4, 142.8, 134.3, 133.1, 132.2, 132.2, 130.9, 128.2, 128.0,
+
1
27.8, 127.8, 127.7, 126.4, 126.4, 126.1, 120.9, 58.0, 52.6, 371.0. ESI - Mass for C20H18N2O6S: m/z [M+Na] :437.3.
Synthesis of methyl(R)-3-(naphthalene-2-yl)-2-((4-nitrophenyl) sulfonamido propanate (4a12)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 3- nitrobenzenesulfonyl chloride (0.58 g, 2.62 mmol),
1
the target product was obtained as a white solid (0.6 g). H NMR (600 MHz, DMSO-d6) δ 9.06 – 8.90 (m, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.72 (d,
J = 8.0 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.57 – 7.48 (m, 3H), 7.45 – 7.33 (m, 2H), 7.30 – 7.24 (m, 1H), 4.27 – 4.16 (m, 1H), 3.59 (s, 3H), 3.23 – 3.11
(m, 1H), 2.92 – 2.75 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.3, 148.2, 146.2, 133.8, 132.4, 131.7, 127.7, 127.6, 127.4, 127.2, 127.1, 1261.0(2C),
+
1
25.8, 125.6, 123.6(2C), 57.6, 52.1, 37.4. ESI - Mass for C20H18N2O6S: m/z [M+Na] : 437.3.
Synthesis of methyl(R)-3-(naphthalene-2-yl)-2-((2-nitrophenyl) sulfonamido propanate (4a13)
Starting material: D-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 2 - nitrobenzenesulfonyl chloride (0.58 g, 2.62 mmol),
1
the target product was obtained as a white solid (0.61 g). H NMR (600 MHz, DMSO-d6) δ 8.85 (d, J = 9.0 Hz, 1H), 7.81 – 7.76 (m, 1H), 7.73 –
7
3
1
.69 (m, 1H), 7.68 – 7.65 (m, 2H), 7.63 – 7.58 (m, 1H), 7.55 – 7.51 (m, 1H), 7.49 – 7.43 (m, 3H), 7.36 – 7.27 (m, 2H), 4.39 – 4.20 (m, 1H), 3.53 (s,
H), 3.27 – 3.18 (m, 1H), 3.08 – 2.98 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 146.6, 1331.0, 133.2, 132.8, 132.7, 131.9, 131.8, 129.0, 127.9,
+
27.6, 127.4, 127.4, 127.4, 125.9, 125.5, 123.7, 57.7, 52.1, 37.3.ESI - Mass for C20H18N2O6S: m/z [M+Na] : 437.3.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-((trifluoromethyl) phenyl)sulfonamide) propanoate (4b1)
Starting material: L - bromophenylalanine methyl ester. (0.3 g, 1.17 mmol) and 2 - nitrobenzenesulfonyl chloride (0.343 g, 1.41 mmol), the
1
target product was obtained as a white solid (0.38 g). H NMR (600 MHz, DMSO-d6) δ 8.79 (d, J = 9.1 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.70 (d,
J = 8.2 Hz, 2H), 7.30 (d, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.09 – 4.00 (m, 1H), 3.44 (s, 3H), 2.99 – 2.91 (m, 1H), 2.78 – 2.66 (m, 1H). 13C NMR (151
MHz, DMSO) δ 1701.0, 144.6, 135.6, 131.8, 131.4, 130.9, 127.0, 126.0, 1251.0, 1251.0, 124.4, 122.6, 119.9, 57.0, 51.9, 36.6. ESI - Mass for
C17H15BrF3NO4S: m/z [M + Na]+ : 488.2/490.3.
10
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Chem. Biodiversity
Synthesis of methyl (R)-3-(4-bromophenyl)-2-((4-methylphenyl)sulfonamido) propanoate(4b2)
Starting material: L - bromophenylalanine methyl ester. (0.3 g, 1.17 mmol) and 4 - methylbenzenesulfonyl chloride (0.27 g, 1.404 mmol),
1
the target product was obtained as a white solid (0.202 g). H NMR (600 MHz, DMSO-d6) δ 8.40 (d, J = 9.0 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H),
7
.34 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 3.99 – 3.87 (m, 1H), 3.41 (s, 3H), 2.94 – 2.85 (m, 1H), 2.78 – 2.65 (m, 1H),
2.37 (s, 3H). 13C NMR (151 MHz, DMSO) δ 1701.0, 142.3, 137.6, 135.6, 131.2, 130.8, 129.1, 1251.0, 119.8, 56.9, 51.7, 36.6, 20.9. ESI - Mass for
+
C17H18BrNO4S: m/z [M+Na] : 434.2/436.2.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-((4-methoxyphenyl) sulfonamide) propanoate(4b3)
Starting material: L - bromophenylalanine methyl ester. (0.3 g, 1.17 mmol) and 4 - methoxylbenzenesulfonyl chloride (0.29 g, 1.404 mmol),
1
the target product was obtained as a white solid (0.38 g). H NMR (600 MHz, DMSO-d6) δ 8.33 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.37
(d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.98 – 3.87 (m, 1H), 3.82 (s, 3H), 3.41 (s, 3H), 2.95 – 2.85 (m, 1H), 2.76 – 2.65
(m, 1H). 13C NMR (151 MHz, DMSO) δ 171.7, 162.5, 136.3, 132.8, 131.9, 131.48, 128.8, 120.4, 114.4, 57.6, 56.1, 52.4, 37.3. ESI - Mass for
+
C17H18BrNO5S: m/z [M+Na] : 450.2/452.3.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-(naphthalene-1-sulfonamido) propanoate (4b4)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and naphthalene - 1 - sulfonyl chloride (0.212 g, 0.936 mmol) in
1
CH2Cl2 (50ml), the target product was obtained as a white solid (0.25 g). H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J = 9.3 Hz, 1H), 8.45 (d, 1H),
8.12 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 6.7, 2.7 Hz, 1H), 7.88 (d, J = 7.3, 1.1 Hz, 1H), 7.70 – 7.56 (m, 2H), 7.52 – 7.45 (m, 1H), 7.00 – 6.93 (m, 2H), 6.85
(d, J = 8.3 Hz, 2H), 3.98 – 3.80 (m, 1H), 3.32 (s, 3H), 2.90 – 2.82 (m, 1H), 2.72 – 2.61 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.3, 135.4, 135.2,
+
1
30.8, 130.4, 128.7, 128.1, 127.4, 127.2, 126.6, 124.7, 124.0, 119.6, 57.2, 51.7, 36.5. ESI - Mass for C20H18BrNO4S: m/z [M+Na] : 470.2/472.3.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-((4-isopropylphenyl) sulfonamido) propanoate(4b5)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and 4 - isopropylbenzenesulfonyl chloride (0.204 g, 0.936
1
mmol)in CH2Cl2 (50ml), the target product was obtained as a white solid (0.27 g). H NMR (600 MHz, DMSO-d6) δ 8.41 (d, J = 9.2 Hz, 1H),
7
1
1
.45 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 5.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 3.98 – 3.86 (m, 1H), 3.37 (s, 3H), 2.98 – 2.92 (m,
H), 2.92 – 2.87 (m, 1H), 2.75 – 2.69 (m, 1H), 1.21 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, DMSO) δ 171.6, 153.5, 138.5, 136.3, 131.9, 131.5,
+
27.2, 126.9, 120.4, 57.5, 52.3, 37.3, 33.8, 231.0, 23.9. ESI - Mass for C19H22BrNO4S: m/z [M + Na] : 462.2/464.2.
Synthesis of methyl (R)-2-([1,1’-biphenyl]-4-sulfonamido)-3-(4-bromophenyl)propanoate(4b6)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and [1, 1’ - biphenyl] - 4 - sulfonyl chloride (0.237 g, 0.936 mmol),
1
the target product was obtained as a white solid (0.26 g). H NMR (600 MHz, DMSO-d6) δ 8.55 (d, J = 9.1 Hz, 1H), 7.74 (t, J = 8.9 Hz, 4H), 7.61
(d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.47 – 7.41 (m, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 4.05 – 3.89 (m, 1H), 3.40 (s, 3H),
2.96 – 2.87 (m, 1H), 2.79 – 2.60 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 143.7, 139.4, 138.5, 135.7, 131.4, 1301.0, 129.1, 128.4, 127.0,
+
1
261.0, 126.8, 119.9, 57.1, 51.8, 36.8.ESI - Mass for C22H20BrNO4S : m/z [M+Na] : 474.3/476.3.
11
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Chemistry & Biodiversity
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Chem. Biodiversity
Synthesis of methyl (R)-3-(4-bromophenyl)-2-(quinolone-8-sulfonamido) propanoate (4b7)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and uinolone - 8 - sulfonyl chloride (0.16 g, 0.696 mmol), the
1
target product was obtained as a white solid (0.22 g). H NMR (500 MHz, DMSO-d6) δ 8.91 (dd, J = 4.2, 1.9 Hz, 1H), 8.47 (d, J = 8.3, 1.9 Hz,
1H), 8.24 – 8.12 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.71 – 7.60 (m, 2H), 7.07 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 4.61 – 4.21 (m, 1H), 2.97 –
1
3
2
.89 (m, 1H), 2.85 – 2.73 (m, 1H). C NMR (151 MHz, DMSO) δ 171.2, 135.3, 133.6, 132.6, 131.7, 128.5, 128.2, 127.4, 127.4, 127.2, 127.0, 126.4,
+
1
25.8, 125.4, 124.54, 123.9, 57.4, 51.6, 37.5. ESI - Mass for C19H17BrN2O4S : m/z [M+Na] : 449.3/451.3.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-((5-bromothiophene)-2-sulfonamido) propanoate (4b8)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and 5 - bromothiophene - 2 - sulfonyl chloride (0.25 g, 0.936
1
mmol), the target product was obtained as a white solid (0.31 g). H NMR (600 MHz, DMSO-d6) δ 8.88 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 8.1 Hz,
2
H), 7.17 – 7.13 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 4.18 – 3.87 (m, 1H), 3.54 (s, 3H), 3.07 – 2.85 (m, 1H), 2.78 – 2.64 (m, 1H). 13C NMR (151 MHz,
DMSO) δ 171.00, 142.6, 135.7, 132.0, 131.4(2C), 131.0 (2C), 130.1, 120.0, 118.4, 57.2, 52.1, 36.6. ESI - Mass for C19H17BrN2O4S : m/z [M+Na]+:
504.1/506.1.
Synthesis of methyl(R)-2-((4-acetamidophenyl) sulfonamide)-3-(4-bromophenyl) propanoate (4b9)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and 4 - acetamidobenzenesulfonyl chloride (0.22 g, 0.936 mmol),
1
the target product was obtained as a white solid (0.23 g). H NMR (600 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.63 (d, 2H), 7.48 (d, 2H), 7.36 (d, 2H),
7
.06 (d, 2H), 3.38 (s, 3H), 2.95 – 2.82 (m, 1H), 2.74 – 2.61 (m, 1H), 2.07 (s, 3H). 13C NMR (151 MHz, DMSO) δ 170.6, 168.4, 142.2, 135.2, 133.8,
+
1
30.9, 130.5, 126.9, 119.4, 117.8, 56.5, 51.4, 36.4, 23.7. ESI - Mass for C18H19BrN2O5S : (m/z) [M+Na] : 477.2/479.2.
Synthesis of methyl(R)-2-((4-acetylphenyl) sulfonamido)-3-(4-bromophenyl) propanoate(4b10)
Starting material: L-bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and 4 - acetamidobenzenesulfonyl chloride (0.204 g, 0.936 mmol),
1
the target product was obtained as a white solid (0.25 g). H NMR (600 MHz, DMSO-d6) δ 8.71 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.61
(d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.9 Hz, 2H), 4.13 – 3.96 (m, 1H), 3.46 (s, 3H), 2.94 (dd, J = 13.8, 5.1 Hz, 1H), 2.70 (dd, J =
1
3.7, 10.1 Hz, 1H), 2.64 (s, 3H). 13C NMR (151 MHz, DMSO) δ 197.2, 171.1, 144.5, 139.0, 135.7, 131.4(2C), 130.9 (2C), 128.6 (2C), 126.3 (2C),
+
1
20.0, 57.2, 52.0, 36.7, 27.0. ESI - Mass for C18H18BrNO5S: (m/z) [M+Na] : 462.3/464.2.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-((3-nitrophenyl) sulfonamido) propanoate(4b11)
Starting material: L - bromophenylalanine methyl ester. (0.2 g, 0.78 mmol) and 3 - nitrobenzenesulfonyl chloride (0.154 g, 0.696 mmol), the
1
target product was obtained as a white solid (0.24 g). H NMR (600 MHz, DMSO-d6) δ 8.97 – 8.85 (m, 1H), 8.43 – 8.36 (m, 1H), 8.23 – 8.17 (m,
1H), 7.98 – 7.90 (m, 1H), 7.78 – 7.60 (m, 1H), 7.25 – 7.20 (m, 2H), 7.11 – 7.00 (m, 2H), 4.21 – 4.03 (m, 1H), 3.50 (s, 3H), 3.00 – 2.91 (m, 1H), 2.76
–
2.63 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.0, 147.4, 135.6, 132.1, 131.4, 130.9, 130.8, 126.5, 120.8, 119.9, 57.1, 52.1, 36.6. ESI - Mass for
+
C16H15BrN2O6S: m/z [M+Na] : 466.3/468.2.
Synthesis of methyl (R)-3-(4-bromophenyl)-2-((4-nitrophenyl) sulfonamide)propanoate(4b12).
12
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Starting material: L - bromophenylalanine methyl ester. (0.15 g, 0.58 mmol) and 4 - nitrobenzenesulfonyl chloride (0.154 g, 0.696 mmol),
1
the target product was obtained as a white solid (0.16 g). H NMR (600 MHz, DMSO-d6) δ 8.53 – 8.35 (m, 1H), 8.04 – 7.88 (m, 1H), 7.51 –
7
.34 (m, 1H), 7.25 – 7.09 (m, 1H), 5.16 (s, 1H), 4.72 – 4.47 (m, 1H), 3.71 (s, 2H), 3.39 – 3.24 (m, 1H), 3.14 – 2.93 (m, 1H). 13C NMR (151 MHz,
DMSO) δ 166.6, 148.9, 146.7, 136.2, 131.3, 130.7, 127.4, 124.1, 119.8, 55.7, 40.0, 37.6. ESI - Mass for C16H15BrN2O6S: m/z [M + Na]+:
66.3/468.2.
4
Synthesis of methyl (R)-3-(4-bromophenyl)-2-((2-nitropheny) sulfonamido) propanoate (4b13)
Starting material: L - bromophenylalanine methyl ester. (0.15 g, 0.58 mmol) and 2 - nitrobenzenesulfonyl chloride (0.154 g, 0.696 mmol),
1
the target product was obtained as a white solid (0.19 g). H NMR (600 MHz, DMSO-d6) δ 8.79 (d, J = 9.0 Hz, 1H), 7.85 – 7.82 (m, 1H), 7.80 –
7
.77 (m, 1H), 7.67 – 7.63 (m, 2H), 7.31 – 7.23 (m, 2H), 7.16 – 7.04 (m, 2H), 4.24 – 4.09 (m, 1H), 3.52 (s, 3H), 3.07 – 2.99 (m, 1H), 2.86 – 2.75 (m,
1H). 13C NMR (151 MHz, DMSO) δ 170.9, 146.8, 135.8, 133.6, 1321.0, 132.3, 131.5, 130.9, 129.3, 124.1, 1191.0, 57.4, 52.1, 36.4. ESI - Mass for
+
C16H15BrN2O6S: m/z [M+Na] : 466.3/468.2.
Synthesis of methyl(R)-3-(4-bromophenyl)-2-(naphthalene-2-sulfonamido) propanoate (4b14)
Starting material: L - bromophenylalanine methyl ester. (0.5 g, 1.95 mmol) and naphthalene - 2 - sulfonyl chloride (0.53 g, 2.34 `mmol), the
1
target product was obtained as a white solid (0.62 g). H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 9.0 Hz, 1H), 8.28 – 8.17 (m, 1H), 8.11 – 7.91
(m, 3H), 7.76 – 7.61 (m, 2H), 7.57 – 7.50 (m, 1H), 7.32 – 7.19 (m, 2H), 7.04 (d, J = 8.1 Hz, 2H), 4.23 – 3.85 (m, 1H), 3.29 (s, 3H), 2.96 – 2.86 (m,
1H), 2.78 – 2.67 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.6, 138.1, 136.1, 134.4, 1311.0, 131.8, 131.4, 129.5, 129.48, 129.1, 128.2, 127.9, 127.4,
+
1
22.4, 120.4, 57.5, 52.3, 37.3.ESI - Mass for C19H17BrN2O4S : m/z [M+Na] : 471.2/473.2.
Synthesis of (R)-3-(4-bromophenyl)-2-((4-bromophenyl) sulfonamido)-N-hydroxypropanamide (4b15)
Starting material: L - bromophenylalanine methyl ester. (0.5 g, 1.95 mmol) and 4 - bromobenzenesulfonyl chloride (0.6 g, 2.34 mmol), the
1
target product was obtained as a white solid (0.49 g). H NMR (600 MHz, DMSO-d6) δ 8.63 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 8.9, 2.5 Hz, 2H),
7
.44 (d, J = 9.0, 2.6 Hz, 2H), 7.35 (d, J = 8.9, 2.5 Hz, 2H), 7.08 (d, J = 8.7, 2.6 Hz, 2H), 4.05 – 3.92 (m, 1H), 3.46 (s, 3H), 2.99 – 2.88 (m, 1H), 2.79
–
2.65 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.5, 140.5, 136.1, 132.3, 131.9, 131.4, 128.6, 126.4, 120.5, 57.5, 52.4, 37.2. ESI - Mass for
+
C16H15Br2NO4S : m/z [M+Na] : 497.9/500.1.
Synthesis of methyl (S)-3-(4-bromophenyl)-2-(naphthalene-2-sulfonamido) propanoate (4d1)
Starting material: D - bromophenylalanine methyl ester (0.3 g, 1.17 mmol) and naphthalene - 2 - sulfonyl chloride (0.32 g, 1.404 mmol), the
1
target product was obtained as a white solid (0.37 g). H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J = 9.1 Hz, 1H), 8.21 (s, 1H), 8.07 (d, J = 8.0 Hz,
1H), 8.01 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.73 – 7.62 (m, 1H), 7.53 (d, J = 8.6, 1.9 Hz, 1H), 7.23 (d, J = 8.8, 2.5 Hz, 2H), 7.04 (d, J = 8.7,
2.6 Hz, 2H), 4.13 – 3.93 (m, 1H), 3.29 (s, 3H), 2.95 – 2.85 (m, 1H), 2.78 – 2.68 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 137.6, 135.6, 133.9,
1
31.4, 131.3(2C), 130.8(2C), 129.0, 128.9, 128.5, 127.7, 127.4, 126.9, 121.9, 119.9, 57.0, 51.7, 36.8. ESI- Mass for C20H18BrNO4S: m/z [M+Na]+:
4
70.4.
Synthesis of methyl (S)-3-(4-bromophenyl)-2-((4-bromophenyl) sulfonamido)propanoate(4d2)
13
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Starting material: D - bromophenylalanine methyl ester (0.3 g, 1.17 mmol) and 4 - bromobenzenesulfonyl chloride (0.36 g, 1.404 mmol), the
1
target product was obtained as a white solid (0.34 g). H NMR (600 MHz, DMSO-d6) δ 8.61 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.43 (d,
J = 8.6 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 8.3 Hz, 2H), 4.04 – 3.93 (m, 1H), 3.45 (s, 3H), 2.96 – 2.87 (m, 1H), 2.75 – 2.66 (m, 1H). 13C
NMR (151 MHz, DMSO) δ 1701.0, 1391.0, 135.6, 131.8(2C), 131.3(2C), 130.9(2C), 128.1(2C), 125.9, 1191.0, 561.0, 51.9, 36.7. ESI - Mass for
+
C20H18BrNO4S : m/z [M+Na] : 498.3.
Synthesis of methyl(S)-3-(4-bromophenyl)-2-((4-trifluoromethyl) phenyl) sulfonamido) propanoate. (4d3)
Starting material: D - bromophenylalanine methyl ester (0.4 g, 1.55 mmol) and 4-(trifluoromethyl) benzenesulfonyl chloride (0.454 g, 1.86
1
mmol), the target product was obtained as a white solid (0.47 g). H NMR (600 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.76 (dd, J = 54.7, 8.1 Hz, 4H),
7
.31 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 4.09 – 4.00 (m, 1H), 3.45 (s, 3H), 3.01 – 2.90 (m, 1H), 2.77 – 2.66 (m, 1H). 13C NMR (151 MHz,
DMSO) δ 1701.0, 144.6, 135.6, 131.8, 131.4(2C), 130.9(2C), 1261.0(2C), 1251.0, 125.9, 123.4, 119.9, 57.0, 51.9, 36.6.ESI - Mass for
+
C17H15BrF3NO4S: m/z [M+Na] : 488.1.
Synthesis of methyl (S)-3-(4-bromophenyl)-2-((4-methylphenyl) sulfonamido)propanoate(4d4)
Starting material: D - bromophenylalanine methyl ester (0.4 g, 1.55 mmol) and 4 - methylbenzenesulfonyl chloride (0.354 g, 1.86 mmol),
1
the target product was obtained as a white solid (0.44 g). H NMR (600 MHz, DMSO-d6) δ 8.39 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.36
–
7.32 (m, 2H), 7.23 (d, J = 7.8 Hz, 2H), 7.07 – 7.03 (m, 2H), 3.92 (td, J = 9.4, 5.7 Hz, 1H), 3.42 (s, 3H), 2.95 – 2.84 (m, 1H), 2.76 – 2.65 (m, 1H),
.37 (s, 3H). 13C NMR (151 MHz, DMSO) δ 171.1, 142.4, 137.8, 135.7, 131.3（2C）, 130.9(2C), 129.2(2C), 126.1(2C), 119.9, 57.0, 51.8, 36.8,
2
+
2
01.0.ESI - Mass for C17H18BrNO4S: m/z [M+Na] : 434.1.
Synthesis of methyl (S)-3-(4-bromophenyl)-2-((3-nitrophenyl) sulfonamido) propanoate (4d5)
Starting material: D - bromophenylalanine methyl ester (0.5 g, 1.95 mmol) and 3 - nitrobenzenesulfonyl chloride (0.52 g, 2.34 mmol), the
1
target product was obtained as a white solid (0.53 g). H NMR (600 MHz, DMSO-d6) δ 8.90 (d, J = 9.0 Hz, 1H), 8.39 (d, J = 8.1, 2.5 Hz, 1H),
8.23 – 8.16 (m, 1H), 7.96 – 7.91 (m, 1H), 7.80 – 7.69 (m, 1H), 7.26 – 7.19 (m, 2H), 7.04 (d, J = 6.6, 4.5 Hz, 2H), 4.19 – 4.09 (m, 1H), 3.50 (s, 3H),
3.03 – 2.93 (m, 1H), 2.76 – 2.64 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 142.4, 137.8, 135.7, 131.3(2C), 130.9(2C), 129.2(2C), 126.1(2C),
+
1
19.9, 57.0, 51.8, 36.8, 201.0. ESI - Mass for C16H15BrN2O6S: m/z [M+Na] : 465.2.
Synthesis of methyl (S)-3-(naphthalene-2-yl)-2-(naphthalene-2-sulfonamido) propanoate(4e1)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.3 g, 1.31 mmol) and naphthalene - 2 - sulfonyl chloride (0.36 g, 1.572
1
mmol), the target product was obtained as a white solid (0.35 g). H NMR (600 MHz, DMSO-d6) δ 8.66 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 1.8 Hz,
1
1
1
H), 7.96 – 7.91 (m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.77 – 7.72 (m, 2H), 7.70 – 7.57 (m, 6H), 7.53 – 7.49 (m, 1H), 7.45 – 7.40 (m, 2H), 7.25 – 7.21 (m,
H), 4.22 – 4.09 (m, 1H), 3.27 (s, 3H), 3.15 – 3.07 (m, 1H), 2.98 – 2.89 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.2, 137.6, 133.8, 133.8, 132.7,
31.8, 131.4, 128.9, 128.8, 128.4, 127.6, 127.6(2C), 127.3, 127.3, 127.2(2C), 126.8, 125.9, 125.5, 121.9, 57.3, 51.7, 37.7. ESI - Mass for
+
C24H21NO4S : m/z [M+Na] : 442.2.
14
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Synthesis of methyl (S)-2-((4-bromophenyl) sulfonamido)-3-(naphthalene-2-yl) propanoate(4e2)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.4 g, 1.57 mmol) and 4 - bromobenzenesulfonyl chloride (0.3 g, 1.31 mmol),
1
the target product was obtained as a white solid (0.48 g). H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 8.8 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.78 –
7
3
1
.75 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.53 – 7.45 (m, 2H), 7.42 – 7.35 (m, 4H), 7.26 (d, J = 8.4 Hz, 1H), 4.16 – 4.06 (m, 1H), 3.46 (s,
H), 3.17 – 3.09 (m, 1H), 2.98 – 2.88 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 139.9, 133.8, 132.7, 131.9, 131.6(2C), 127.9(2C), 127.7, 127.6,
+
27.4, 127.3, 127.3, 126.0, 125.8, 125.6, 57.3, 51.9, 37.6. ESI - Mass for C20H18BrNO4S: m/z [M+Na] : 470.2/472.3.
Synthesis of methyl (S)-3-(naphthalene-2-yl)-2-((4-(trifluoromethyl) phenyl) sulfonamido)Propanoate (4e3)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.3 g, 1.31 mmol) and 4-(trifluoromethyl) benzenesulfony chloride (0.384
1
g, 1.572 mmol), the target product was obtained as a white solid (0.36 g). H NMR (600 MHz, DMSO-d6) δ 8.86 (d, J = 9.0 Hz, 1H), 7.84 –
7.78 (m, 1H), 7.77 – 7.72 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 3H), 7.54 (d, J = 8.1 Hz, 2H), 7.49 – 7.44 (m, 2H), 7.32 – 7.16 (m,
1H), 4.22 – 4.10 (m, 1H), 3.45 (s, 3H), 3.22 – 3.10 (m, 1H), 2.96 – 2.88 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.1, 144.6, 133.8, 132.7, 131.8,
131.6, 127.7, 127.6, 127.3, 127.3, 126.9, 1251.0, 125.7, 125.6, 125.6, 123.3, 57.3, 51.9, 37.5. ESI - Mass for C21H18F3NO4S: m/z [M+Na]+:
4
50.3.
Synthesis of methyl (S)-2-((4-methylphenyl) sulfonamido)-3-(naphthalene-2-yl) propanoate(4e4)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.3 g, 1.31 mmol) and 4 - methylbenzenesulfonyl chloride (0.3 g, 1.572
1
mmol), the target product was obtained as a white solid (0.38 g). H NMR (600 MHz, DMSO-d6) δ 8.46 (d, J = 8.9 Hz, 1H), 7.87 – 7.82 (m, 1H),
7
.78 – 7.70 (m, 2H), 7.61 – 7.57 (m, 1H), 7.51 – 7.44 (m, 2H), 7.40 – 7.34 (m, 2H), 7.27 – 7.21 (m, 1H), 7.06 – 7.01 (m, 2H), 4.08 – 3.99 (m, 1H),
3.40 (s, 3H), 3.13 – 3.05 (m, 1H), 2.96 – 2.86 (m, 1H), 2.22 (s, 3H). 13C NMR (151 MHz, DMSO) δ 171.2, 142.2, 137.7, 133.9, 132.8, 131.9,
+
1
281.0(2C), 127.6, 127.6, 127.4(2C), 127.3, 126.1(2C), 125.9, 125.5, 57.3, 51.7, 37.7, 20.8. ESI - Mass for C21H21NO4S : m/z [M+Na] : 406.2.
Synthesis of methyl (S)-2-((4-methoxyphenyl) sulfonamido)-3-(naphthalene-2-yl) propanoate(4e5)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.3 g, 1.31 mmol) and 4 - methoxylbenzenesulfonyl chloride (0.324 g, 1.572
1
mmol), the target product was obtained as a white solid (0.31 g). H NMR (600 MHz, DMSO-d6) δ 8.39 (d, J = 9.0 Hz, 1H), 7.89 – 7.82 (m, 1H),
7
.80 – 7.71 (m, 2H), 7.60 (s, 1H), 7.52 – 7.38 (m, 4H), 7.30 – 7.24 (m, 1H), 6.80 – 6.74 (m, 2H), 4.08 – 3.98 (m, 1H), 3.71 (s, 3H), 3.41 (s, 3H), 3.16
–
3.04 (m, 1H), 2.98 – 2.87 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.3, 161.8, 133.9, 132.8, 132.3, 131.9, 128.3(2C), 127.7, 127.6, 127.4(2C),
+
1
25.9(2C), 125.5, 113.7(2C), 57.3, 55.4, 51.8, 37.7.ESI - Mass for C21H21NO5S: m/z [M+Na] : 422.4.
Synthesis of methyl(S)-3-(naphthalene-2-yl)-2-((3-nitrophenyl) sulfonamido) propanoate (4e6)
Starting material: L-Napthylalanine hydrochloride methyl ester (0.5 g, 2.18 mmol) and 3 - nitrobenzenesulfonyl chloride (0.58 g, 2.62 mmol),
1
the target product was obtained as a white solid (0.62 g). H NMR (600 MHz, DMSO-d6) δ 8.95 (d, J = 9.0 Hz, 1H), 8.11 – 8.07 (m, 1H), 7.97 –
7
1
1
.88 (m, 1H), 7.83 – 7.79 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 – 7.58 (m, 2H), 7.54 (s, 1H), 7.47 – 7.38 (m, 3H), 7.29 – 7.23 (m, 1H), 4.32 – 4.13 (m,
H), 3.54 (s, 3H), 3.21 – 3.09 (m, 1H), 2.93 – 2.78 (m, 1H). 13C NMR (151 MHz, DMSO) δ 171.2, 146.9, 142.3, 133.7, 132.6, 131.7, 130.4, 127.7,
+
27.5, 127.3（2C）, 127.2, 125.9, 125.9, 125.6, 120.4(2C), 57.6, 52.1, 37.5. ESI - Mass for C20H18N2O6S : m/z [M+Na] : 437.2.
15
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Synthesis of ethyl(naphthalene-2-ylsulfonyl)-D-tyrosinate (5c1)
Starting material: D - tyrosine ethyl ester hydrochloride (0.3 g, 1.32 mmol) and naphthalene-2-sulfonyl chloride (0.39 g, 1.584 mmol), the
+
target product was obtained as a white solid (0.48 g). ESI - Mass for C21H21NO5S : m/z [M+Na] : 422.4.
Synthesis of ethyl ((4-bromophenyl) sulfonyl)-D-tyrosinate (5c2)
Starting material: D - tyrosine ethyl ester hydrochloride (0.25 g, 1.01 mmol) and 4 - bromobenzenesulfonyl chloride (0.34 g, 1.404 mmol),
+
the target product was obtained as a white solid (0.35 g). ESI - Mass for C17H18BrNO5S: m/z [M+Na] : 426.2/428.2.
Synthesis of ethy ((4-trifluoromethyl) phenyl) sulfonyl)-D-tyrosinate (5c3)
Starting material: D - tyrosine ethyl ester hydrochloride (0.5 g, 2.04 mmol) and 4 - (trifuoromethyl) benzenesulfonyl chloride (0.6 g, 2.448
+
mmol), the target product was obtained as a white solid (0.48 g).ESI - Mass for C18H18F3NO5S: m/z [M+Na] : 440.3.
Synthesis of ethyl tosyl-D-tyrosinate (5c4)
Starting material: D - tyrosine ethyl ester hydrochloride (0.5 g, 2.04 mmol) and 4 - methylbenzenesulfonyl chloride (0.772 g, 3.14 mmol), the
+
target product was obtained as a white solid (0.52 g). ESI - Mass for C17H18BrNO5S : m/z [M+Na] : 386.3.
Synthesis of ethyl ((4-methoxyphenyl) sulfonyl)-D-tyrosinate. (5c5)
Starting material: D - tyrosine ethyl ester hydrochloride (0.5 g, 2.04 mmol) and 4 - methoxybenzenesulfonyl chloride (0.78 g, 3.14 mmol),
+
the target product was obtained as a white solid (0.49 g).ESI - Mass for C18H21NO6S: m/z [M+Na] : 402.4.
General synthesis of compounds 6a-b,d-e and 7c
The material (4a1) was dissolved in Methanol (5 mL) and Tetrahydrofuran (5 mL), 10 mL of aqueous hydroxylamine (50 percent w/w) was
added. The mixture was stirred for 24 h at rt, then concentrated onto silica, chromatographed (2 percent to 10 percent MeOH /CH2Cl2 ),
and dried to provide white solid( Yield 63.1%).
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-((4-(trifluoromethyl) phenyl)sulfonamide) propanamide(6a1)
Starting material: 4a1 (0.2 g, 0.458 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), the target product was obtained as a
white solid (0.15 g, Yield 63.1%).1H NMR (600 MHz, DMSO) δ 10.73 (s, 1H), 8.95 (s, 1H), 8.67 (s, 1H), 7.78 (d, J = 6.2 Hz, 1H), 7.71 (d, J = 6.3 Hz,
1H), 7.63 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 5.3 Hz, 3H), 7.49 – 7.40 (m, 5H), 7.22 (d, J = 7.9 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.01 – 2.92 (m, 1H), 2.88 –
2.79 (m, 1H). 13C NMR (151 MHz, DMSO) δ 167.4, 145.4, 131.0, 133.2, 132.2, 131.8, 128.2, 127.9, 127.9, 127.8, 127.7, 127.2, 126.4, 126.0, 1251.0,
-
1
25.9, 124.7, 122.9, 56.2, 39.0.HRMS (ESI): calcd for C20H17F3N2O4S [M-H] : 437.0782; found, 437.0976.
Synthesis of (R)-N-hydroxy-2-((4-methylphenyl) sulfonamido)-3-(naphthalene-2-yl) propanamide (6a2)
Starting material: 4a2 (0.26 g, 0.679 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.2 g, Yield
35.4 %).1H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.90 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.73 – 7.70 (m, 1H), 7.67 (d, J =
16
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
8.4 Hz, 1H), 7.52 (s, 1H), 7.50 – 7.43 (m, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 – 7.19 (m, 1H), 6.92 (d, J = 7.9 Hz, 2H), 3.93 – 3.79 (m, 1H), 2.99 –
2.89(m, 1H), 2.80 – 2.70 (m, 1H), 2.17 (s, 3H). 13C NMR (151 MHz, DMSO) δ 167.5, 142.3, 138.7, 135.0, 133.3, 132.4, 129.4(2C), 129.2, 128.0,
-
1
28.0, 127.9, 127.9, 127.8, 126.4(2C), 126.3, 125.9, 56.0, 39.1, 21.3.HRMS (ESI): calcd for C20H20N2O4S [M-H] : 383.1065; found, 383.1060.
Synthesis of (R)-N-hydroxy-2-((4-methoxyphenyl) sulfonamide)-3-(naphthalene-2-yl) propanamide. (6a3)
Starting material: 4a3 (0.25 g, 0.627 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.22 g, Yield
1
5
8.1 %). H NMR (600 MHz, DMSO) δ 7.79 (d, J = 1.5 Hz, 1H), 7.75 (dt, J = 7.5, 1.5 Hz, 2H), 7.70 (dd, J = 7.4, 1.4 Hz, 1H), 7.45 (td, J = 7.4, 1.6 Hz,
1H), 7.42 – 7.34 (m, 4H), 7.32 – 7.27 (m, 2H), 5.65 (s, 1H), 4.56 (s, 1H), 4.47 – 4.39 (m, 1H), 3.80 (s, 3H), 3.72 – 3.60 (m, 1H), 3.15 – 2.98 (m, 1H).
13C NMR (151 MHz, DMSO) δ 137.7, 134.8, 134.3, 133.1, 129.5(2C), 128.6, 127.9, 127.6, 127.4, 126.2, 126.1, 125.1, 115.6(2C), 59.7, 55.4, 37.8
-
HRMS (ESI): calcd for C20H20N2O5S [M-H] : 399.1014; found, 399.1011.
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-(quinolone-8-sulfonamido) propanamide (6a4)
Starting material: 4a4 (0.34 g, 0.81 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.3 g, Yield
55 %).1H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.82 (dd, J = 4.3, 1.7 Hz, 1H), 8.24 (dd, J = 8.3, 1.7 Hz, 1H), 8.08 (dd, J = 7.3, 1.4 Hz, 1H),
8
.04 – 7.99 (m, 1H), 7.73 – 7.67 (m, 1H), 7.61 – 7.56 (m, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.47 – 7.42 (m, 2H), 7.44 – 7.39 (m, 4H), 7.11 – 7.06 (m, 1H),
.45 (s, 1H), 4.42 – 4.08 (m, 1H), 2.99 – 2.93 (m, 1H), 2.90 – 2.83 (m, 1H). 13C NMR (151 MHz, DMSO) δ 167.5, 151.2, 142.7, 137.2, 136.9, 134.6,
6
133.7, 1321.0, 132.1, 129.7, 128.7, 128.0, 127.9, 127.8, 127.6, 127.5, 126.2, 125.9, 125.6, 122.5, 56.7, 39.4.HRMS (ESI): calcd for C22H19N3O4S
-
[
M - H] :420.1017; found, 420.1021.
Synthesis of (R)-N-hydroxy-2-((4-isopropylphenyl) sulfonamide)-3-(naphthalene-2-yl) propanamide (6a5)
Starting material: 4a5 (0.15 g, 0.36 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.1 g, Yield
1
4
4.2 %). H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.91 (s, 1H), 7.87 – 7.83 (m, 1H), 7.78 – 7.73 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H),
7
.49 – 7.45 (m, 2H), 7.37 (d, J = 7.9 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.9 Hz, 2H), 3.93 – 3.81 (m, 1H), 2.99 – 2.91 (m, 1H), 2.84 – 2.70
(
m, 2H), 1.18 – 1.04 (m, 7H). 13C NMR (151 MHz, DMSO) δ 167.1, 152.4, 138.6, 134.7, 132.7, 131.8, 127.6, 127.6, 127.5, 127.4, 127.3, 126.4 (2C),
126.2 (2C), 125.9, 125.4, 55.5, 38.6, 33.1, 23.4, 23.3. HRMS (ESI): calcd for C22H24N2O4S[M-H]-: 411.1378; found, 411.1396.
Synthesis of (R)-2-([1, 1’-biphenyl]-4-sulfonamido)-N-hydroxy-3-(naphthalene-2-yl) propanamide (6a6)
Starting material: 4a6 (0.26 g, 0.58 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.22 g, Yield
1
6
1.3 %). H NMR (600 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 7.75 – 7.70 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 – 7.53 (m, 3H),
7
.53 – 7.46 (m, 4H), 7.44 – 7.34 (m, 5H), 7.24 (dd, J = 8.4, 1.7 Hz, 1H), 3.99 – 3.85 (m, 1H), 3.02 – 2.91 (m, 1H), 2.88 – 2.74 (m, 1H). 13C NMR (151
MHz, DMSO) δ 167.0, 143.2, 139.9, 138.4, 134.6, 132.8, 131.8, 128.9 (2C), 128.3 (2C), 127.6, 127.6, 127.5, 127.3, 127.3, 126.9 (2C) 126.6, 126.6
-
:
(
2C), 125.9, 125.3, 55.6, 38.6. HRMS (ESI) : calcd for C25H22N2O4S [M - H] 445.1221; found, 445.1224.
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-(naphthalene-1-sulfonamido) propanamide (6a7)
Starting material: 4a7 (0.27 g, 0.6 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.2 g, Yield
1
5
2.4 %). H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.91 (d, J = 1.5 Hz, 1H), 8.62 (d, J = 9.0 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.2
17
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 8.1, 1.5 Hz, 1H), 7.70 – 7.67 (m, 1H), 7.56 – 7.51 (m, 1H), 7.45 – 7.34 (m, 7H), 7.31 – 7.27 (m, 1H), 7.01
13
–
6.97 (m, 1H), 3.96 – 3.86 (m, 1H), 2.93 – 2.86 (m, 1H), 2.76 – 2.67 (m, 1H). C NMR (151 MHz, DMSO) δ 167.71, 136.39, 134.77, 133.95, 133.79,
133.00, 132.05, 128.84, 128.16, 127.84, 127.81 (2C), 127.68, 127.64, 127.52, 127.51, 126.81, 126.11, 125.71, 125.23, 124.26, 56.11, 39.09. HRMS
-
:
(
ESI): calcd for C23H20N2O4S [M - H] 419.1065; found, 419.1062.
Synthesis of (R)-2-((5-bromothiophene)-2-sulfonamido)-N-hydroxy-3-(naphthalene-2-yl) propanamide (6a8)
Starting material: 4a8 (0.2 g, 0.44 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.18 g, Yield
6
2.8 %).1H NMR (600 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.97 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 14.3, 8.2 Hz, 2H),
.62 (s, 1H), 7.53 – 7.43 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 3.9 Hz, 1H), 6.88 (d, J = 3.9 Hz, 1H), 3.98 – 3.91 (m, 1H), 3.02 – 2.96 (m, 1H),
.88 – 2.81 (m, 1H). 13C NMR (151 MHz, DMSO) δ 167.2, 143.5, 1341.0, 133.3, 132.3, 1311.0, 1301.0, 128.2, 128.0, 1271.0, 1271.0, 127.8, 126.48,
251.0, 118.3, 56.3, 381.0.HRMS (ESI): calcd for C17H15BrN2O4S2[M-H]-: 452.9578; found, 452.9574/454.9532.
7
2
1
Synthesis of (R)-2-((4-acetamidophenyl) sulfonamide)-N-hydroxy-3-(naphthalene-2-yl) propanamide (6a9)
Starting material: 4a9 (0.31 g, 0.73 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.18 g, Yield
4
7.9 %).1H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.10 (s, 1H), 8.87 (s, 0H), 7.83 – 7.79 (m, 1H), 7.74 – 7.68 (m, 3H), 7.52 (s, 1H), 7.45 (d,
J = 7.3 Hz, 6H), 7.21 (d, J = 8.4 Hz, 1H), 4.01 – 3.75 (m, 1H), 2.98 – 2.91 (m, 1H), 2.78 – 2.71 (m, 1H), 2.06 (s, 3H). 13C NMR (151 MHz, DMSO) δ
69.2, 167.3, 142.8, 135.3, 1341.0, 133.3, 132.3, 128.0, 1271.0, 1271.0, 127.8, 127.8, 127.6(2C), 126.3, 125.9, 118.6, 55.9, 39.1, 24.6.HRMS (ESI):
1
calcd for C21H21N3O5S[M-H]-: 426.1123; found, 426.1137.
Synthesis of (R,E)-N-hydroxy-2-((4-(1-(hydroxyimino) ethyl)phenyl) sulfonamido)-3-(naphthalene-2-yl) propanamide (6a10).
Starting material: 4a10 (0.35 g, 0.85 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.27 g, Yield
1
4
4.6 %). H NMR (600 MHz, DMSO-d6) δ 11.49 (s, 1H), 10.69 (s, 1H), 8.93 (s, 1H), 8.25 (s, 1H), 7.81 – 7.78 (m, 1H), 7.74 – 7.71 (m, 1H), 7.68 (d,
J = 8.4 Hz, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.48 – 7.40 (m, 6H), 7.25 – 7.21 (m, 1H), 3.97 – 3.88 (m, 1H), 3.01 – 2.93 (m, 1H), 2.84 – 2.77 (m, 1H), 2.06
s, 3H). 13C NMR (151 MHz, DMSO) δ 167.4, 152.3, 141.3, 140.3, 135.0, 133.3, 132.3, 128.1, 128.0, 1271.0, 127.8, 127.8, 126.5(2C), 126.3(2C),
25.9(2C), 56.1, 39.1, 11.8.HRMS (ESI): calcd for C21H21N3O5S[M-H]-: 426.1123; found, 426.1142.
(
1
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-(3-nitrophenyl) sulfonamide propanmide (6a11)
Starting material: 4a11 (0.25 g, 0.61 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.23 g, Yield
1
5
3.3 %). H NMR (600 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.13 – 8.07 (m, 1H), 7.90 – 7.82 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H),
7
.71 (d, J = 7.7 Hz, 1H), 7.63 – 7.54 (m, 2H), 7.48 (s, 1H), 7.45 – 7.38 (m, 2H), 7.38 – 7.34 (m, 1H), 7.26 – 7.21 (m, 1H), 4.06 – 3.91 (m, 1H), 3.00 –
2.88 (m, 1H), 2.87 – 2.76 (m, 1H). 13C NMR (151 MHz, DMSO) δ 167.3, 147.2, 143.1, 134.9, 133.0, 132.1, 132.1, 130.6, 128.1, 127.9, 127.9, 127.8,
1
27.6, 126.4, 126.2, 126.0, 120.9, 56.5, 38.9. HRMS (ESI) : calcd for C21H21N3O5S [M - H]- : 414.0759; found, 414.0779.
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-(4-nitrophenyl)sulfonamide propanamide(6a12)
18
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Chemistry & Biodiversity
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Chem. Biodiversity
Starting material: 4a12 (0.3 g, 0.72 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.19 g, Yield
1
4
2.7 %). H NMR (600 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.97 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 – 7.58 (m, 2H), 7.54 –
7
.45 (m, 3H), 7.43 – 7.31 (m, 2H), 7.25 (d, J = 8.5 Hz, 1H), 4.02 – 3.91 (m, 1H), 2.99 – 2.90 (m, 1H), 2.88 – 2.77 (m, 1H). 13C NMR (151 MHz,
DMSO) δ 1661.0, 148.1, 146.5, 134.4, 132.4, 131.7, 127.7, 127.6(2C), 127.1(2C), 126.9(2C), 125.8, 125.5, 123.5(2C), 56.2, 38.4.HRMS (ESI ): calcd
for C21H21N3O5S[M-H]-: 414.0759; found, 414.0768.
Synthesis of (R)-N-hydroxy-3-(naphthalene-2-yl)-2-(4-nitrophenyl)sulfonamide propanamide (6a13)
Starting material: 4a13 (0.32 g, 0.77 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.22 g, Yield
1
4
7 %). H NMR (600 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.97 (s, 1H), 8.19 (s, 0H), 7.82 – 7.76 (m, 1H), 7.71 – 7.68 (m, 1H), 7.66 (d, 2H), 7.57 (d, J =
8.0, 1.2 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.48 – 7.41 (m, 3H), 7.32 (d, J = 8.3, 1.8 Hz, 1H), 7.27 – 7.22 (m, 1H), 4.08 – 4.00 (m, 1H), 3.06 – 3.01 (m,
1H), 2.99 – 2.94 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 146.6, 134.4, 133.1, 133.0, 132.6, 131.8(2C), 128.8, 127.8, 127.6, 127.5, 127.4,
127.3, 125.9, 125.4, 123.7, 56.3, 38.5.HRMS (ESI) : calcd for C21H21N3O5S[M-H]-: 414.0759; found, 414.0765.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((trifluoromethyl) phenyl) sulfonamio) propanamide (6b1)
Starting material: 4b1 (0.23 g, 0.49 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.2 g, Yield
1
4
9.7 %). H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.95 (s, 1H), 8.60 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.3
Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 3.83 – 3.74 (m, 1H), 2.79 – 2.71 (m, 1H), 2.67 – 2.60 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 1441.0, 136.2,
-
1
31.3(2C), 130.8(2C), 126.8(2C), 125.9, 125.9, 124.4, 122.6, 119.7, 55.5, 37.7. HRMS (ESI) : calcd for C16H14BrF3N2O4S [M - H] :464.9731;
found, 464.9716/466.9686.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((4-methylphenyl) sulfonamide) propanamide (6b2)
Starting material: 4b2 (0.15 g, 0.36 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.14 g, Yield
1
6
8.1 %). H NMR (600 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.91 (s, 1H), 8.09 (s, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1
Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 3.76 – 3.66 (m, 1H), 2.76 – 2.67 (m, 1H), 2.62 – 2.52 (m, 1H), 2.37 (s, 3H). 13C NMR (151 MHz, DMSO) δ 166.9,
42.0, 138.3, 136.3, 131.3, 130.7, 129.1, 1251.0, 119.7, 55.3, 37.7, 21.0. HRMS (ESI) : calcd for C16H17BrN2O4S[M-H]-: 411.0013; found,
11.0001/466.0024.
1
4
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((4-methoxyphenyl) sulfonamide) propanamide (6b3)
Starting material: 4b3 (0.22 g, 0.52 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.2 g, Yield
1
6
6.2 %). H NMR (600 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.46 – 7.41 (m, 2H), 7.34 – 7.30 (m, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.92 – 6.88 (m, 2H),
3.82 (d, J = 6.3 Hz, 3H), 3.75 – 3.64 (m, 1H), 2.77 – 2.68 (m, 1H), 2.58 – 2.52 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.9, 161.8, 136.4, 132.9,
-
1
31.4, 130.8, 128.2, 119.6, 113.8, 55.5, 55.3, 37.7.HEMS (ESI) : calcd for C16H17BrN2O4S [M - H] :411.0013; found, 411.0001/466.0000.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-(naphthalene-1-sulfonamido) propanamide(6b4)
Starting material: 4b4 (0.15 g, 0.33 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.12 g, Yield
1
6
5.3 %). H NMR (600 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 6.6
19
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Chemistry & Biodiversity
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Chem. Biodiversity
Hz, 1H), 7.63 – 7.53 (m, 2H), 7.48 – 7.42 (m, 1H), 6.80 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 3.76 – 3.68 (m, 1H), 2.67 – 2.60 (m, 1H), 2.56
–
2.51 (m, 1H). 13C NMR (151 MHz, DMSO) δ 167.9, 136.3, 136.3, 134.1, 133.8, 131.1, 130.5, 129.2, 128.2, 127.7, 127.7, 126.9, 125.5, 124.4, 119.8,
-
5
6.2, 38.1.HRMS (ESI): (m/z): [M - H] :calcd for C20H18BrNO4S, 447.0013; found, 447.0038/448.9980.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((4-isopropylphenyl) sulfonamido) propanamide (6b5)
Starting material: 4b5 (0.15 g, 0.33 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.12 g, Yield
1
4
0.2 %). H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.92 (s, 1H), 8.16 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.3
Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 3.69 (dd, J = 9.1, 5.5 Hz, 1H), 2.99 – 2.90 (m, 1H), 2.72 (dd, J = 13.6, 5.4 Hz, 1H), 2.56 (dd, J = 13.5, 9.4 Hz, 1H),
1.22 (d, J = 6.9 Hz, 6H). 13C NMR (151 MHz, DMSO) δ 167.0, 152.6, 138.6, 136.4, 131.4, 130.8, 126.5, 126.2, 119.6, 55.3, 37.7, 33.3, 23.5,
-
2
3.4.HRMS (ESI) : calcd for C18H21BrN2O4S, [M - H] :439.0326; found, 439.0333/441.0288.
Synthesis of (R)-2-([1, 1’-biphenyl]-4-sulfonamido)-3-(4-bromophenyl)-N-hydroxypropanamide (6b6)
Starting material: 4b6 (0.18 g, 0.38 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.16 g, Yield
1
6
2.7 %). H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.92 (s, 1H), 8.31 (s, 1H), 7.73 (d, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H),
7
.51 (t, J = 7.7 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.03 (t, J = 7.7 Hz, 2H), 3.84 – 3.73 (m, 1H), 2.82 – 2.72 (m, 1H), 2.64 – 2.55
m, 1H). 13C NMR (151 MHz, DMSO) δ 167.3, 143.9, 140.4, 139.1, 136.8, 131.9, 131.3, 129.5, 128.8, 127.5, 127.4, 127.2, 120.2, 55.9, 38.3.
(
-
:
HRMS (ESI) : calcd for C21H19BrN2O4S, [M - H] 473.017; found, 473.0164/475.0136.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-(quinolone-8-sulfonamido) propanamide (6b7)
Starting material: 4b7 (0.15 g, 0.33 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.1 g, Yield
1
5
7.5 %). H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.99 – 8.76 (m, 2H), 8.46 (d, J = 8.3, 1.7 Hz, 1H), 8.19 (d, J = 8.2, 1.4 Hz, 1H), 8.10 (d, J
=
7.2, 1.4 Hz, 1H), 7.73 – 7.57 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.25 – 4.06 (m, 1H), 2.85 – 2.58 (m, 2H). 13C NMR (151
MHz, DMSO) δ 167.0, 150.9, 142.3, 1361.0, 136.7, 135.8, 133.3, 130.9, 130.1, 129.3, 128.3, 125.2, 122.3, 119.5, 56.1, 37.9.HRMS (ESI) : calcd for
C18H16BrN3O4S[M-H]-: 447.9966; found, 447.9954/449.9977.
Synthesis of (R)-3-(4-bromophenyl)-2-((5-bromothiophene)-2-sulfonamido-N-hydroxypropanamide (6b8)
Starting material: 4b8 (0.15 g, 0.32 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.07 g, Yield
1
3
7.5 %). H NMR (600 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.97 (s, 1H), 8.64 (s, 1H), 7.45 – 7.34 (m, 2H), 7.16 – 7.03 (m, 4H), 3.90 – 3.73 (m, 1H),
2
.81 – 2.74 (m, 1H), 2.69 – 2.62 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.6, 143.1, 136.3, 131.6, 131.4 (2C), 130.9 (2C), 130.7, 119.8, 118.0,
-
:
5
5.6, 37.6. HRMS (ESI) : calcd for C13H12Br2N2O4S2 [M - H] 4480.8526; found, 480.8544/482.8506/484.8457.
Synthesis of (R)-2-((4-acetamidophenyl) sulfonamido)-3-(4-bromophenyl)-N-hydroxypropanamide (6b9)
Starting material: 4b9 (0.15 g, 0.33 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.14 g, Yield
1
4
4
7.3 %). H NMR (600 MHz, DMSO-d6) δ 7.59 – 7.55 (m, 1H), 7.49 – 7.44 (m, 1H), 7.30 (dt, J = 7.6, 1.1 Hz, 1H), 6.72 – 6.54 (m, 1H), 5.90 (s, 1H),
.75 (s, 1H), 4.68 – 4.60 (m, 1H), 4.51 (s, 1H), 3.57 – 3.46 (m, 0H), 3.26 – 3.11 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 152.3, 136.4, 131.3
20
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
-
:
(
2C), 130.8 (2C), 128.2 (2C), 126.2, 119.6, 112.4 (2C), 54.9, 37.7. HRMS (ESI) : [M - H] - calcd for C17H18BrN3O5S [M - H] 454.0072; found,
4
54.0096/456.0027.
Synthesis of (R)-2-((4-acetyphenyl) sulfonamide)-3-(4-bromophenyl)-N-hydroxypropanamide(6b10)
Starting material: 4b10 (0.15 g, 0.34 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.075 g, Yield
1
3
1
1
6.7 %). H NMR (600 MHz, DMSO-d6) δ 8.14 – 8.08 (m, 1H), 7.99 – 7.89 (m, 1H), 7.43 – 7.32 (m, 1H), 7.21 – 7.09 (m, 1H), 5.46 (s, 1H), 4.77 (s,
H), 4.52 – 4.30 (m, 1H), 3.64 – 3.41 (m, 1H), 2.99 – 2.80 (m, 1H), 2.51 (s, 2H). 13C NMR (151 MHz, DMSO) δ 197.4, 172.7, 144.3, 138.3, 132.9,
-
:
31.7 (2C), 131.2 (2C), 128.5 (2C), 127.4 (2C), 120.1, 59.7, 38.1, 26.8. HRMS (ESI) : calcd for C15H16BrN3O4S [M - H] 411.9966; found,
4
12.0013/414.0038.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((3-nitrophenyl) sulfonamide propanamide(6b11)
Starting material: 4b11 (0.15 g, 0.34 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.075 g, Yield
1
4
8
2
6.7 %). H NMR (600 MHz, DMSO-d6) δ 10.70 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.74 (d, J = 9.0 Hz, 1H), 8.46 – 8.31 (m, 1H), 8.22 –
.14 (m, 1H), 7.98 – 7.87 (m, 1H), 7.77 – 7.62 (m, 1H), 7.27 – 7.13 (m, 2H), 7.01 – 6.92 (m, 2H), 4.00 – 3.71 (m, 1H), 2.77 – 2.70 (m, 1H), 2.67 –
.59 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.4, 147.3, 142.7, 136.2, 1311.0, 131.3, 130.7, 130.7, 126.3, 120.8, 119.7, 55.6, 37.6. HRMS (ESI) :
calcd for C13H12Br2N2O4S2 [M - H] - : 441.9708; found, 440.9971/482.8506/438.9957.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((4-nitrophenyl) sulfonamido)propanamide(6b12)
Starting material: 4b12 (0.15 g, 0.34 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.1 g, Yield
4
1.7 %).1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.92 (s, 1H), 8.75 (s, 1H), 8.25 – 8.16 (m, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 7.9 Hz,
H), 7.00 (d, J = 8.2 Hz, 2H), 2.78 – 2.70 (m, 1H), 2.67 – 2.59 (m, 1H). 13C NMR (151 MHz, DMSO) δ 172.7, 150.0, 143.3, 132.9, 131.7(2C),
2
131.2(2C), 128.3(2C), 126.3(2C), 120.1, 581.0, 52.5, 39.5. HRMS (ESI) : calcd for C15H14BrN3O6S[M-H]-: 441.9708; found, 441.9710/443.9728.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-((2-nitropheny) sulfonamido) propanamide(6b13)
Starting material: 4b13 (0.15 g, 0.34 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.083 g, Yield
1
4
1.1 %). H NMR (600 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.95 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.63 – 7.58 (m, 2H), 7.28 – 7.22
(m, 2H), 7.17 – 7.01 (m, 2H), 3.97 – 3.83 (m, 1H), 2.90 – 2.68 (m, 2H). 13C NMR (151 MHz, DMSO) δ 166.6, 146.8, 136.1, 133.4, 133.2, 132.2,
131.4, 130.7, 129.1, 124.1, 119.8, 56.1, 37.6.HRMS (ESI) : calcd for C15H14BrN3O6S[M-H]-: 441.9708; found, 441.9708/443.9738.
Synthesis of (R)-3-(4-bromophenyl)-N-hydroxy-2-(naphthalene-2-sulfonamido) propanamide(6b14)
Starting material: 4b14 (0.15 g, 0.33 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.23 g, Yield
1
6
4.1 %). H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 8.17 (s, 1H), 8.03 – 7.97 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.70 –
7
.63 (m, 2H), 7.52 – 7.47 (m, 1H), 7.17 – 7.12 (m, 2H), 6.98 – 6.92 (m, 2H), 3.86 – 3.76 (m, 1H), 2.77 – 2.70 (m, 1H), 2.64 – 2.56 (m, 1H). 13C NMR
(
151 MHz, DMSO) δ 166.9, 138.2, 136.2, 133.9, 131.4, 131.3, 130.7, 1281.0, 128.9, 128.4, 127.8, 127.3, 126.6, 121.9, 119.7, 55.4, 37.8. HRMS
ESI) : calcd for C19H17BrN2O4S[M-H]-: 447.0013; found, 447.0018/449.0024.
(
21
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Synthesis of (R)-3-(4-bromophenyl)-2-((4-bromophenyl) sulfonamido)-N-hydroxypropanamide (6b15)
Starting material: 4b15 (0.15 g, 0.315 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.16 g, Yield
1
4
3.2 %). H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.92 (s, 1H), 8.41 (s, 1H), 7.63 – 7.55 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.8, 2.6
Hz, 2H), 7.01 (d, J = 6.6, 4.3 Hz, 2H), 3.75 (s, 1H), 2.77 – 2.70 (m, 1H), 2.64 – 2.56 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 140.4, 136.2,
-
1
31.7, 131.3, 130.8, 127.9, 125.7, 119.8, 55.4, 37.7.HRMS (ESI): calcd for C15H14Br2N2O4S [M - H] :474.8962; found, 474.8969/476.8975.
Synthesis of (S)-3-(4-bromophenyl)-N-hydroxy-2-(naphthalene-2-sulfonamido) propanamide(6d1)
Starting material: 4d1 (0.3 g, 0.67 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.25 g, Yield
1
4
8.5 %). H NMR (600 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.18 – 8.14 (m, 1H), 7.99 (d, J = 13.8, 8.0 Hz, 2H), 7.88 (d, J = 8.7 Hz, 1H), 7.70 – 7.60 (m,
2H), 7.51 – 7.45 (m, 1H), 7.14 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 7.9 Hz, 2H), 3.85 – 3.76 (m, 1H), 2.76 – 2.68 (m, 1H), 2.64 – 2.55 (m, 1H). 13C NMR
(151 MHz, DMSO) δ 166.8, 138.2, 136.2, 133.9, 131.4, 131.2(2C), 130.6(2C), 1281.0, 128.9, 128.4, 127.7, 127.3, 126.6, 121.9, 119.7, 55.4,
37.8.HRMS (ESI) : calcd for C19H17BrN2O4S[M-H]-: 447.0013; found, 447.0036/448.9977.
Synthesis of (S)-3-(4-bromophenyl-2-((4-bromophenyl)sulfonamido)-N-hydroxypropanamide(6d2)
Starting material: 4d2 (0.25 g, 0.56 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.19 g, Yield
1
4
1.2 %). H NMR (600 MHz, /llkjm,n) δ 10.65 (s, 1H), 8.91 (s, 1H), 8.39 (s, 1H), 7.63 – 7.56 (m, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.34 – 7.28 (m, 2H),
7
.01 (d, J = 8.1 Hz, 2H), 3.78 – 3.71 (m, 1H), 2.77 – 2.69 (m, 1H), 2.65 – 2.57 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 140.4, 136.2, 131.7(2C),
31.3(2C), 130.8(2C), 127.9(2C), 125.7, 119.8, 55.4, 37.7.HRMS (ESI) calcd for C15H14Br2N2O4S[M-H]-: 474.9322; found,
74.8968/476.8973/478.8939.
1
:
4
Synthesis of (S)-3-(4-bromophenyl)-N-hydroxy-2-((4-(trifluoromethyl) phenyl) sulfonamido)propanamide (6d3)
Starting material: 4d3 (0.15 g, 0.32 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.1 g, Yield
1
6
0.1 %). H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.94 (s, 1H), 8.44 (s, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.8
Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 3.82 – 3.75 (m, 1H), 2.78 – 2.70 (m, 1H), 2.66 – 2.59 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 1441.0, 136.2,
31.6, 131.3, 130.7, 126.8, 125.8, 125.8, 123.5, 119.6, 55.5, 37.7.HRMS (ESI) : calcd for C17H17BrF2N2O4S[M-H]-: 464.9731; found,
64.9733/466.9724.
1
4
Synthesis of (S)-3-(4-bromophenyl)-N-hydroxy-2-((4-methylphenyl) sulfonamido)propanamide (6d4)
Starting material: 4d4 (0.15 g, 0.36 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.24 g, Yield
1
4
8.3 %). H NMR (600 MHz, DMSO-d6) δ 8.88 (s, 1H), 7.37 (d, J = 7.7 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 7.7 Hz, 2H), 6.97 (d, J = 7.8 Hz,
2
H), 6.50 (s, 1H), 3.78 – 3.68 (m, 1H), 2.71 (dd, J = 13.4, 5.5 Hz, 1H), 2.56 (dd, J = 13.6, 9.3 Hz, 1H), 2.37 (s, 3H). 13C NMR (151 MHz, DMSO) δ
166.9, 142.0, 138.3, 136.3, 131.3(2C), 130.7(2C), 129.1(2C), 1251.0(2C), 119.7, 55.4, 37.7, 21.0. HRMS (ESI) : calcd for C16H17BrF2N2O4S [M-
-
H] : 411.0013; found, 411.0007/413.0022.
Synthesis of (S)-3-(4-bromophenyl)-N-hydroxy-2-((3-nitrophenyl) sulfonamido)propanamide(6d5)
22
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Starting material: 4d5 (0.4 g, 0.36 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.36 g, Yield
1
5
3.4 %). H NMR (600 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.91 (s, 1H), 8.40 – 8.33 (m, 1H), 8.24 – 8.13 (m, 1H), 7.96 – 7.86 (m, 1H), 7.77 – 7.67 (m,
1
H), 7.20 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.45 (s, 1H), 3.92 – 3.71 (m, 1H), 2.77 – 2.68 (m, 1H), 2.67 – 2.61 (m, 1H). 13C NMR (151
MHz, DMSO) δ 167.0, 147.8, 143.3, 136.7, 132.5, 131.8（2C）, 131.3, 131.2 (2C), 126.9, 121.3, 120.2, 56.16, 38.1. HRMS (ESI) : calcd for
C15H14BrN3O6S[M-H]-: 441.9708; found, 441.9693/443.9632.
Synthesis of (S)-N-hydroxy-3-(naphthalene-2-yl)-2-(naphthalene-2-sulfonamido) propanamide (6e1)
Starting material: 4e1 (0.2 g, 0.48 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.18 g, Yield
1
3
8.6 %). H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.87 (s, 1H), 8.42 – 8.32 (m, 1H), 8.14 (s, 1H), 7.84 (dd, J = 18.6, 8.1 Hz, 2H), 7.72 – 7.68
(m, 1H), 7.64 – 7.54 (m, 4H), 7.54 – 7.48 (m, 2H), 7.47 – 7.36 (m, 3H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 4.14 – 3.87 (m, 1H), 3.00 – 2.91 (m, 1H), 2.82
13
–
2.71 (m, 1H). C NMR (151 MHz, DMSO) δ 166.9, 138.2, 134.5, 133.8, 132.8, 131.7, 131.4, 128.9, 128.6, 128.3, 127.6, 127.5, 127.4, 127.3, 127.30,
-
1
27.2, 127.2, 126.6, 125.8, 125.4, 121.9, 55.6, 38.6. HRMS (ESI) : calcd for C23H20N2O4S [M-H] : 419.1065; found, 419.1059.
Synthesis of (S)-2-((4-bromophenyl) sulfonamido)-N-hydroxy-3-(naphthalene-2-yl) propanamide (6e2)
Starting material: 4e2 (0.2 g, 0.45 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.17 g, Yield 42 %).
1H NMR (600 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.91 (s, 1H), 7.87 – 7.81 (m, 1H), 7.75 – 7.71 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.52 –
7
.44 (m, 2H), 7.35 – 7.27 (m, 4H), 7.24 – 7.16 (m, 1H), 3.92 – 3.81 (m, 1H), 2.99 – 2.91 (m, 1H), 2.85 – 2.72 (m, 1H). 13C NMR (151 MHz, DMSO)
δ 166.8, 140.3, 134.5, 132.7, 131.8, 131.4(2C), 127.8(2C), 127.6, 127.4, 127.4, 127.4, 127.2, 125.9, 125.5, 125.5, 55.6, 38.6. HRMS (ESI) : calcd for
C19H17BrN2O4S[M-H]-: 447.0013; found, 447.0030/448.0085.
Synthesis of (S)-N-hydroxy-3-(naphthalene-2-yl)-2-((4-(trifluoromethyl)phenyl)sulfonamido)propanamide (6e3)
Starting material: 4e3 (0.15 g, 0.34 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.1 g, Yield 43 %).
1H NMR (600 MHz, DMSO-d6) δ 8.00 – 7.94 (m, 1H), 7.84 – 7.77 (m, 1H), 7.78 – 7.72 (m, 1H), 7.70 (dd, J = 7.5, 1.4 Hz, 0H), 7.48 – 7.43 (m, 1H),
7
.42 – 7.37 (m, 0H), 7.31 (d, J = 7.5, 1.4 Hz, 0H), 5.59 (s, 0H), 4.81 (s, 0H), 4.51 – 4.38 (m, 1H), 3.78 – 3.63 (m, 1H), 3.14 – 2.98 (m, 1H). 13C NMR
(151 MHz, DMSO) δ 172.7, 144.8, 136.5, 134.8, 134.3, 133.1, 128.6, 128.1, 128.1, 127.9, 127.6, 127.4, 126.7, 126.6, 126.5, 126.4, 126.2, 126.1,
-
1
25.1, 123.2, 59.7, 37.8. HRMS (ESI) : calcd for C19H17BrN2O4S [M - H] : 438.0861; found, 437.0782/437.0774.
Synthesis of (S)-N-hydroxy-2-((4-methyphenyl) sulfonamido)-3-(naphthalene-2-yl) propanamide (6e4)
Starting material: 4e4 (0.2 g, 0.52 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.18 g, Yield
1
4
4 %). H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.89 (s, 1H), 8.17 (s, 1H), 7.88 – 7.80 (m, 1H), 7.75 – 7.63 (m, 2H), 7.54 – 7.43 (m, 3H), 7.33
(
d, J = 7.8 Hz, 2H), 7.23 – 7.17 (m, 1H), 6.92 (d, J = 7.9 Hz, 2H), 3.87 (dd, J = 8.9, 5.7 Hz, 1H), 2.98 – 2.88 (m, 1H), 2.82 – 2.67 (m, 1H), 2.17 (s,
H). 13C NMR (151 MHz, DMSO) δ 1661.0, 141.8, 138.2, 134.5, 132.8, 131.8, 128.9(2C), 127.5, 127.6, 127.4, 127.3, 127.3, 125.9(2C), 125.8, 125.3,
5.5, 38.6, 20.8.HRMS (ESI) : calcd for C20H20N2O4S [M - H] - : 383.1065; found, 383.1057.
3
5
Synthesis of (S)-N-hydroxy-2-((4-methoxyphenyl) sulfonamido)-3-(naphthalene-2-yl) propanamide. (6e5)
23
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
Starting material: 4e5(0.15 g, 0.375 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.13 g, Yield
1
4
6 %). H NMR (600 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.87 (s, 1H), 7.88 – 7.81 (m, 1H), 7.77 – 7.67 (m, 2H), 7.53 (s, 1H), 7.49 – 7.43 (m, 3H), 7.41
–
7.37 (m, 2H), 7.23 – 7.19 (m, 1H), 6.66 (d, J = 8.9 Hz, 2H), 3.90 – 3.81 (m, 1H), 3.68 (s, 3H), 2.99 – 2.91 (m, 1H), 2.78 – 2.70 (m, 1H). 13C NMR
(151 MHz, DMSO) δ 166.9, 161.5, 134.6, 132.9, 132.8, 131.8, 128.1(2C), 127.6, 127.5, 127.4, 127.3, 127.3, 125.8, 125.4, 113.5(2C), 55.5, 55.3,
38.6.HRMS (ESI) : calcd for C20H20N2O5S[M-H]-: 399.1014; found, 399.1030.
Synthesis of (S)-N-hydroxy-3-(naphthalene-2-yl)-2-((3-nitrophenyl) sulfonamido) propanamide (6e6)
Starting material: 4e6(0.15 g, 0.36 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.12 g, Yield
1
4
4.6 %). H NMR (600 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.94 (s, 1H), 8.75 (s, 1H), 8.13 – 8.06 (m, 1H), 7.88 – 7.84 (m, 1H), 7.80 – 7.77 (m, 1H),
7
.73 – 7.70 (m, 1H), 7.61 – 7.56 (m, 2H), 7.48 – 7.47 (m, 1H), 7.44 – 7.38 (m, 2H), 7.38 – 7.34 (m, 1H), 7.26 – 7.21 (m, 1H), 4.07 – 3.90 (m, 1H), 2.97
–
2.89 (m, 1H), 2.85 – 2.76 (m, 1H). 13C NMR (151 MHz, DMSO) δ 166.7, 146.7, 142.6, 134.4, 132.5, 131.6, 131.6, 130.2, 127.6, 127.4, 127.4,
-
1
27.3, 127.1, 125.9, 125.7, 125.5, 120.4, 551.0, 38.4. HRMS (ESI) : calcd for C19H17N3O5S [M - H] :414.0759; found, 414.0758.
Synthesis of (R)-N-hydroxy-3-(4-hydroxyphenyl)-2-(naphthalene-2-sulfonamido) propanamide (7c1)
Starting material: 5c1 (0.3 g, 0.78 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.21 g, Yield
1
4
9.5 %). H NMR (600 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.21 (d, 2H), 8.11 (d, J = 8.2 Hz, 1H), 7.89 – 7.85 (m, 1H), 7.81 – 7.76 (m, 1H), 7.74 – 7.68
(m, 1H), 7.19 – 7.09 (m, 2H), 6.96 – 6.86 (m, 2H), 3.27 – 3.08 (m, 1H), 2.86 – 2.71 (m, 1H), 2.65 – 2.52 (m, 1H). 13C NMR (151 MHz, DMSO) δ
170.9, 147.4, 138.2, 1341.0, 131.6, 131.4(2C), 130.7, 130.1, 129.9, 129.9, 129.6, 128.0, 1271.0, 122.5, 121.48(2C), 54.1, 40.4.HRMS (ESI) : calcd
for C19H18N2O5S[M-H]-: 385.0857; found, 385.0844.
Synthesis of (R)-2-((4-bromophenyl) sulfonamido)-N-hydroxy-3-(4-hydroxyphenyl) propanamide (7c2)
Starting material: 5c2 (0.25 g, 0.59 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.17 g, Yield
1
4
3.2 %). H NMR (600 MHz, DMSO-d6) δ 7.90 – 7.85 (m, 2H), 7.78 – 7.72 (m, 2H), 7.20 (d, 2H), 6.94 (d, 2H), 3.25 – 3.15 (m, 1H), 2.85 – 2.73 (m,
1H), 2.65 – 2.55 (m, 1H). 13C NMR (151 MHz, DMSO) δ 170.8, 147.2, 138.4, 133.6, 132.9(2C), 130.8(2C), 130.0(2C), 129.1, 121.5(2C), 54.1, 40.5.
HRMS (ESI) : [M - H] - calcd for C15H15BrN2O5S[M-H]-: 412.9806; found, 412.9836/414.9799.
Synthesis of (R)-N-hydroxy-3-(4-hydroxyphenyl)-2-((4-(trifluoromethyl) phenyl) sulfonamido)propanamide (7c3)
Starting material: 5c3 (0.4 g, 0.96 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.32 g, Yield
1
5
7.8 %). H NMR (600 MHz, DMSO-d6) δ 8.19 – 7.96 (m, 4H), 7.29 – 7.13 (m, 2H), 7.01 – 6.88 (m, 2H), 3.24 – 3.16 (m, 1H), 2.85 – 2.74 (m, 1H),
2.67 – 2.57 (m, 1H). 13C NMR (151 MHz, DMSO) δ 170.8, 147.1, 138.6, 138.3, 134.5, 130.8(2C), 129.2(2C), 1261.0, 126.9, 121.5(2C), 54.1,
-
:
4
0.5.HRMS (ESI) : calcd for C16H15F3N2O5S [M - H ] 403.0575; found, 403.0577.
Synthesis of (R)-N-hydroxy-3-(4-hydroxyphenyl)-2-((4-methylphenyl) sulfonamido) propanamide (7c4)
Starting material: 5c4 (0.4 g, 1.1 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.36 g, Yield 44.4 %).
1H NMR (600 MHz, DMSO-d6) δ 7.81 – 7.69 (m, 2H), 7.46 (d, J = 7.9 Hz, 2H), 7.24 – 7.14 (m, 2H), 6.96 – 6.85 (m, 2H), 3.24 – 3.15 (m, 1H), 2.86
24
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Chemistry & Biodiversity
10.1002/cbdv.201800646
Chem. Biodiversity
–
2.74 (m, 1H), 2.64 – 2.55 (m, 1H), 2.42 (s, 3H). 13C NMR (151 MHz, DMSO) δ 170.9, 147.4, 145.6, 138.1, 131.6, 130.6(2C), 130.1(2C), 128.1(2C),
121.5(2C), 54.1, 40.6, 21.1.HRMS (ESI) : calcd for C16H18N2O5S[M-H]-: 349.0857; found, 349.0860.
Synthesis of (R)-N-hydroxy-3-(4-hydroxyphenyl)-2-((4-methoxyphenyl) sulfonamide) propanamide (7c5)
Starting material: 5c5 (0.3 g, 0.75 mmol) and 10 mL of aqueous hydroxylamine (50 percent w/w), obtained as white solid (0.25 g, Yield
1
5
5.1 %). H NMR (600 MHz, DMSO-d6) δ 7.77 – 7.72 (m, 2H), 7.21 – 7.13 (m, 4H), 6.92 – 6.87 (m, 2H), 3.87 (s, 3H), 3.24 – 3.16 (m, 1H), 2.83 –
2.73 (m, 1H), 2.66 – 2.54 (m, 1H). 13C NMR (151 MHz, DMSO) δ 170.8, 163.9, 147.4, 138.0, 130.6(2C), 130.5(2C), 125.6, 121.5(2C), 114.9(2C),
55.9, 54.1, 40.5.HRMS (ESI) : calcd for C16H18N2O6S[M-H]-: 365.0807; found, 365.0812.
Acknowledgements
The research was supported by the National Natural Science Foundation of China (81473098, 81473099 and 81703366), the Fundamental
Research Funds for the Central Universities (332017078), Fundamental Research Funds for Jinzhou Medical University (JYTQN201731) and
CAMS innovation fund for Medical Sciences (2016-I2M-3-014, 2016-I2M-1-011, and 2017-I2M-3-019)
Author Contribution Statement
Duan-Yang Shao, Dong-Hui Li,Ju-Xian Wang and Yu-Cheng Wang designed and planned the experiments. Duan-Yang Shao, Guo-Ning
Zhang, Mei Zhu and Zi-Qiang Li synthesized the compounds.Wei-Xiao Niu tested their cytotoxic effect. Duan-Yang Shao wrote the the
manuscript with support from Guo-Ning Zhang and Dong-Hui Li. Yucheng Wang supervised the project.
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Entry for the Graphical Illustration
O
O
OH
OH
N
N
H
H
NH
S
NH
S
Br
O
O
O
O
O
R
R
R''
NH2
O
O
O
HN
OH
OH
S
N
N
O
H
H
R'
NH
S
NH
S
O
O
Br
O
2
-(sulfonamido) propanamide
R
R
O
Most promissing cytotoxic compounds against HepG2, HT1080, KB, and
value of 30
MCF-7 cells with an IC50
SRB) assay
µM range in the sulforhodamine B
(
26
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