Total Synthesis and Anti-inflammatory Evaluation of Penchinone A and Its Structural Analogues

Article abstract of DOI:10.1021/acs.joc.7b02212

The first total synthesis and biological evaluation of penchinone A and its structural analogues are described. The key steps for the preparation of penchinone A derivatives involve the oxime-directed palladium(II)-catalyzed oxidative acylation, Claisen r

Full text of DOI:10.1021/acs.joc.7b02212

Subscriber access provided by UNIV TORONTO
Article
Total Synthesis and Anti-inflammatory Evaluation
of Penchinone A and Its Structural Analogs
Yongguk Oh, Yeon Jeong Jang, Mijin Jeon, Hyung Sik Kim, Jong Hwan
Kwak, Kyu Hyuck Chung, Suhkneung Pyo, Young Hoon Jung, and In Su Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02212 • Publication Date (Web): 11 Oct 2017
Downloaded from http://pubs.acs.org on October 11, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 20
The Journal of Organic Chemistry
Total Synthesis and Anti-inflammatory Evaluation of Penchinone A and Its
1
2
3
4
Structural Analogs
5
6
7
8
9
Yongguk Oh,a Yeon Jeong Jang,a Mijin Jeon,a Hyung Sik Kim,a Jong Hwan Kwak,a Kyu Hyuck
Chung,a Suhkneung Pyo,a,* Young Hoon Jung,a,b,* and In Su Kima,*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
b Biocenter, Gyeonggido Business & Science Accelerator (GBSA), Suwon 16229, Republic of Korea
* Corresponding authors. E-mails: snpyo@skku.edu (S.Pyo), yhjung@skku.edu (Y.H.Jung), insukim@skku.edu
(I.S.Kim)
Keywords: Acylation; Anti-inflammatory; Natural Product; Penchinone; Total Synthesis.
C-H acylation
O
Me
olefin
migration
O
O
Me
7 steps
HO
OH
Me
OMe
OH
Claisen
OH
rearrangement
penchinone A
O
Me
O
For NO production inhibition:
IC50 = 1.81 M (R1 = OH, R2 = OMe, R3 = H)
IC50 = 0.94 M (R1 = H, R2 = H, R3 = OH)
IC50 = 1.01 M (R1 = OH, R2 = OMe, R3 = OH)
Me
R1
R3
R2
OH
Abstract
The first total synthesis and biological evaluation of penchinone A and its structural analogs are
described. The key steps for the preparation of penchinone A derivatives involve the oxime-directed
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 20
palladium(II)-catalyzed oxidative acylation, Claisen rearrangement and base-mediated olefin migration.
This transformation efficiently provides a range of allyl-substituted biaryl ketones with site-selectivity
and functional group compatibility. In addition, all synthetic compounds were screened for anti-
inflammatory activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6
(IL-6) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of penchinone A
derivatives potently inhibited NO, TNF-α, and IL-6 productions, compared to dexamethasone as a
positive control. Notably, penchinone A (8g) and its derivatives (8e and 8f) were found to exhibit
powerful anti-inflammatory property stronger than that of dexamethasone.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Introduction
Lignans have been known as the important class of naturally occurring phenylpropanoid dimers, and
play a crucial role in the biological defence of plants against external pathogens and pests.1 In addition,
these compounds have been known to possess a variety of pharmacological effects, such as anti-
inflammatory, anti-tumoral, antimitotic, antiviral, antiatherosclerotic activities and etc.2 Although the
framework of lignans consists only of two phenylpropane (C6−C3) units, lignans exhibit a wide range of
structural diversity by the linkage patterns derived from the oxidative coupling of two C6−C3 units.
Figure 1. Structure of penchinone A and its derivatives.
Penchinones A−D were firstly isolated from the hepatoprotective portion of the water decoction of
Penthorum chinense Pursh by Xiong and coworkers in 2015 (Figure 1).3 Traditionally, Penthorum
2
ACS Paragon Plus Environment

Page 3 of 20
The Journal of Organic Chemistry
chinense Pursh has been used as a folk medicine for the treatment of hepatic and gallbladder diseases in
China.4 Penchinones A−D show the unique structural feature including two pairs of cis-trans isomers
with rearranged carbon skeletons. Notably, the presence of 1,2-bis-acyl and internal trans-allyl groups on
penchinone A encourages the organic and medicinal chemists to synthesize this complex molecule.
Biaryl ketones have been recognized as crucial structural motifs in biologically active compounds
and functional materials.5 Recently, the transition-metal-catalyzed oxidative acylation reactions of sp2
C−H bonds have been intensively studied for the construction of biaryl ketones.6 For example, our group
firstly reported the Rh(III)-catalyzed oxidative acylation of benzamides using aryl aldehydes as acyl
sources to afford biaryl ketone compounds.7 Later, the Pd(II)-catalyzed acylation reactions of aromatic
compounds using various acyl surrogates such as aldehydes, alcohols, ethers and toluene derivatives were
also explored under the oxidative conditions.8 Generally, tert-butyl hydroperoxide (TBHP) was widely
used as an oxidant to generate the acyl radical intermediates, delivering the acyl moiety on sp2 C−H
bonds. In continuation to our recent works on the discovery of biologically active compounds based on
the catalytic C−H functionalization,9 we herein describe the first total synthesis of penchinone A and its
structural analogs via the Pd(II)-catalyzed oxidative acylation of ketoximes with aldehydes. In addition,
all synthetic compounds were evaluated for the inhibitory activity against nitric oxide (NO), tumor
necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) with lipopolysaccharide (LPS)-induced
RAW264.7 cells,10 and were found to potently inhibit NO, TNF-α, and IL-6 productions without affecting
the viability of RAW264.7 cells, competitive with well-known dexamethasone as a positive control.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and discussion
The total synthesis of penchinone A was initiated by the formation of ketoxime 5a (Scheme 1).
Allylation of p-hydroxyacetophenone (1) followed by the subsequent Claisen rearrangement affored
ortho-allylated phenol 2 in 71% yields for two steps. Olefin migration of 2 was performed by the
treatment of KOtBu providing internal olefin 3 with a ratio of E:Z = 5:1 in 95% yield. The reaction of 3
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 20
with O-methyl hydroxylamine hydrochloride smoothly provided p-hydroxy ketoxime 4, which was
further acetylated to afford a separable mixture of trans-adduct 5a (71%) and cis-adduct 5b (14%),
respectively.
1
2
3
4
5
6
7
8
9
O
Me
O
Me
O
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1) allyl bromide, K2CO3
MeCN, 60 oC, 6 h
KOtBu, THF
2) o-xylene, 220 oC, 18 h
80 oC, 8 h
Me
95% (E:Z = 5:1)
71%
OH
1
OH
OH
2
3
OMe
OMe
OMe
N
N
Me
N
Me
Me
MeONH2•HCl
NaOAc
AcCl, DIPEA
CH2Cl2
+
Me
60 oC, 6 h
MeOH, rt, 4 h
Me
Me
87% (E:Z = 5:1)
OH
OAc
5a (71%)
OAc
5b (14%)
4
Scheme 1. Synthesis of ketoxime 5a.
Next, we performed the ketoxime-directed catalytic oxidative acylation of 5a using para-
anisaldehyde (6a) as a model substrate (Table 1). As shown in entry 1, no coupling reaction between 5a
and 6a under cationic Rh(III) catalysis was observed. In addition, treatment of Ag2CO3 as an external
oxidant was found to be ineffective in this transformation (Table 1, entries 2 and 3). To our delight, this
coupling reaction was detected by using Pd(II) catalyst and TBHP oxidant to provide our desired product
7a in 38% yield (Table 1, entry 4). Increasing amount of TBHP to 3 equiv. provided an improved yield
(51%) of the acylated adduct 7a (Table 1, entries 5 and 6). Further screening of additive and Pd salts was
found to be less effective in this reaction (Table 1, entries 7 and 8). Notably, an increased loading of
Pd(OAc)2 to 10 mol % displayed the increased reactivity, giving 7a in 61% yield (Table 1, entry 9).
Subsequently, various solvents were screened, and 1,2-dichloroethane (DCE) solvent was found to be
most effective (Table 1, entries 10–12). Furthermore, we performed the control experiments to increase
the yield of 7a, but no improvement of acylated product 7a was observed, as shown in entries 13 and 14.
4
ACS Paragon Plus Environment

Page 5 of 20
The Journal of Organic Chemistry
Finally, this reaction was also carried out either under N2 atmosphere or by using molecular sieves, and
no improved yield of both reactions was observed (Table 1, entries 15 and 16). Meanwhile, the C−H
acylation reaction of phenol compound 4 was also examined under various reaction conditions. However,
no formation of the corresponding adduct was detected, presumably due to the tight bidentate
coordination of both hydroxy and olefin functionality to a Pd(II) center.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Selected optimization of reaction conditions.a
Entry
Catalyst (mol %)
Additive (mol %)
Solvent
Yield (%)b
1
2
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
[RhCp*Cl2]2 (2.5)
Pd(OAc)2 (5)
AgSbF6 (10)
AgSbF6 (10), Ag2CO3 (200)
AgSbF6 (10), Ag2CO3 (200)
TBHP (200)
DCE
DCE
N.R.
N.R.
N.R.
38
3
THF
4
DCE
5
Pd(OAc)2 (5)
TBHP (300)
DCE
51
6
Pd(OAc)2 (5)
TBHP (400)
DCE
50
7
Pd(OAc)2 (5)
TBHP (300), AcOH (200)
TBHP (300)
DCE
32
8
Pd(OTf)2 (5)
DCE
31
9
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
TBHP (300)
DCE
THF
61
10
11
12
13c
14d
15e
TBHP (300)
25
TBHP (300)
1,4-dioxane
MeOH
DCE
21
TBHP (300)
trace
55
TBHP (300)
TBHP (300)
DCE
60
TBHP (300)
DCE
48
16f
TBHP (300)
DCE
43
a
Reaction conditions: 5a (0.2 mmol), 6a (0.6 mmol), catalyst (quantity noted), additive (quantity noted),
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 20
solvent (1 mL) under air at 80 oC for 20 h in pressure tubes. b Isolated yield by flash column chromatography. c The
1
2
3
o
d
e
reaction was carried out at 120 C. 6a (1 mmol, 5 equiv.) was used. The reaction was carried out under N2
4
5
atmosphere. f The reaction was carried out under air using 4Å molecular sieves.
6
7
8
9
OMe
5a
O
Me
N
Me
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Pd(OAc)2 (10 mol %)
TBHP (3 equiv)
+
0.5 M HCl
MeOH/acetone
80 oC, 4 h
O
R
R
DCE, 80 oC, 20 h
H
Me
R
Me
OH
OAc
7a 7g
6a-6g
8a-8g, %
-
, %
C-H acylation
OMe
N
OMe
N
OMe
OMe
Me
Me
N
Me
N
O
Me
O
O
O
R1
Me
HO
Me
OH
Me HO
OH
Me
R2
OAc
OMe
OAc
OAc
OMe
OAc
7a, 61% (R1 = OMe, R2 = H)
7b, 51% (R1 = OH, R2 = H)
7c, 49% (R1 = H, R2 = OMe)
7d, 40% (R1 = H, R2 = OH)
7e, 34%
7f, 21%
7g, 18%
Hydrolysis
O
Me
O
O
Me
O
Me
O
Me
O
O
O
R1
Me
HO
Me
OH
Me HO
OH
Me
R2
OH
OMe
OH
8e, 55%
OH
OMe
OH
8a, 53% (R1 = OMe, R2 = H)
8b, 71% (R1 = OH, R2 = H)
8c, 40% (R1 = H, R2 = OMe)
8d, 45% (R1 = H, R2 = OH)
8f, 61%
8g, 60%
(penchinone A)
Scheme 2. Synthesis of penchinone A derivatives via C−H acylation and hydrolysis.
With the optimal reaction conditions for the oxidative C−H acylation reaction in hand, various aryl
aldehydes 6b−6g were coupled with ketimine 5a (Scheme 2). The para-OH-substituted benzaldehyde 6b
was found to display moderate reactivity furnishing the biaryl ketone 7b in 51% yield. The acylation
reaction of meta-substituted benzaldehydes 6c and 6d showed relatively decreased reactivity under the
current reaction conditions to afford the corresponding products 7c and 7d. Additionally, 3,4-
6
ACS Paragon Plus Environment

Page 7 of 20
The Journal of Organic Chemistry
disubstituted substrate 6e also underwent the C–H acylation reaction to deliver the desired adduct 7e in
34% yield. Notably, ortho-hydroxybenzaldehyde (6f) was also tolerable in this transformation to provide
7f, albeit resulting in low yield (21%). Moreover, this method can be successfully applied to a highly
substituted benzaldehyde 6g to yield 7g as a synthetic precursor of penchinone A (8g). To construct
penchinone A and its structural analogs, we performed the acid-mediated hydrolysis of all acylated
compounds 7a–7g. Acetyl and imine moieties were readily removed by using 0.5 M HCl in
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
MeOH/acetone at 80 C to furnish the corresponding products 8a–8g in moderate to good yields. The
spectroscopic data (1H NMR and 13C NMR) and physical properties of the synthesized penchinone A (8g)
were in full agreement with the reported values.3
Table 2. Inhibitory effects of the synthesized compounds 7a–7g and 8a–8g on NO, TNF-α, and IL-6 in
LPS-induced RAW264.7 cells.a
IC50 value (µM)
TNF-α
IC50 value (µM)
TNF-α
compounds
compounds
NO
IL-6
NO
IL-6
7a
7b
7c
7d
7e
7f
7.60 0.07 11.16 0.06 8.68 0.06
6.26 0.02 8.66 0.07 5.60 0.01
2.73 0.01 5.89 0.01 4.26 0.02
2.78 0.02 6.96 0.02 4.14 0.02
5.77 0.02 8.97 0.07 6.88 0.02
4.95 0.01 4.32 0.02 3.23 0.02
4.16 0.07 6.24 0.02 5.96 0.01
8a
8b
8c
8d
8e
8f
4.38 0.02 9.16 0.04 7.66 0.01
5.40 0.01 7.66 0.01 6.53 0.01
2.00 0.02 4.05 0.00 2.15 0.03
6.21 0.03 6.86 0.02 7.70 0.01
1.81 0.01 3.77 0.02 3.10 0.01
0.94 0.01 3.20 0.03 2.07 0.01
1.01 0.01 3.12 0.01 2.10 0.04
7g
8g
dexamethasone 1.76 0.02 4.52 0.02 3.92 0.01
a IC50 value (µM): 50% inhibition concentration for NO, TNF-α, and IL-6 production. The results are reported
as mean value SEM for n = 3.
Synthetic penchinone A and its derivatives (7a–7g and 8a–8g) were evaluated for in vitro inhibitory
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 20
activity against nitric oxide (NO), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) as cell
signaling cytokines involved in inflammation process (Table 2). Inflammation has been known as an early
response of host against pathogenic challenge.11 In this process, activated inflammatory cells can secrete
increased amounts of NO, prostaglandins, and cytokines such as IL-1β, IL-6, and TNF-α. In our
experiment, the anti-inflammatory activity was determined by enzyme-linked immunosorbent
assay (ELISA) using LPS-induced RAW264.7 cells, and represents the 50% inhibition concentration of
compounds compared with LPS-stimulated cells (see Figure S1 in Supporting Information for dose-
dependent cell viability data of 7a–7g and 8a–8g). A commercial anti-inflammatory drug, dexamethasone,
was selected as a positive control.12 A range of compounds (7c, 7d, 8c and 8e–8g) exhibited comparable
inhibitory activity with dexamethasone. In particular, penchinone A (8g) and its structural analog (8f)
were found to display most potent inhibitory activities (IC50 = 1.01 0.01 µM for 8g and IC50 = 0.94
0.01 µM for 8f) against NO production, stronger than that of a positive control (see Figure S2 in
Supporting Information for dose-dependent NO production inhibition data). Moreover, compounds (8c
and 8e–8g) were found to induce higher inhibition activity than that of dexamethasone against TNF-α and
IL-6 productions (see Figures S3 and S4 in Supporting Information for dose-dependent TNF-α and IL-6
production inhibition data). Based on the structure-activity relationship (SAR) between synthetic
compounds (8c and 8e–8g), we believe that the o-hydroxy and/or m-methoxy groups on the left ring of
penchinone A are very crucial for anti-inflammatory activity.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusion
In conclusion, we described the first total synthesis and anti-inflammatory evaluation of penchinone
A and its structural derivatives via the oxime-directed palladium(II)-catalyzed oxidative acylation, the
Claisen rearrangement, and base-mediated olefin migration. This transformation efficiently provides an
array of allyl-substituted biaryl ketones with site-selectivity and functional group compatibility. In
addition, all synthetic compounds were screened for inhibitory activity against NO, TNF-α, and IL-6
8
ACS Paragon Plus Environment

Page 9 of 20
The Journal of Organic Chemistry
productions with LPS-induced RAW264.7 cells. Notably, penchinone A (8g) and its derivatives (8e and
8f) were found to display potent anti-inflammatory activity stronger than that of dexamethasone as a
positive control.
1
2
3
4
5
6
7
8
9
Experimental Section
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental procedure and characterization data for the synthesis of 2: To an oven-dried
round bottom flask (100 mL) charged with para-hydroxyacetophenone (1) (2.7 g, 20 mmol, 100 mol %),
K2CO3 (5.5 g, 40 mmol, 200 mol %) and MeCN (20 mL) was added allyl bromide (2.1 mL, 24 mmol, 120
o
mol %) under air at room temperature. The reaction mixture was allowed to stir for 6 h at 60 C. The
resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated
NH4Cl solution (2 × 60 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc = 2:1) to afford the 1-(4-(allyloxy)phenyl)ethan-1-one
(3.5 g, 99%) as a colorless oil. Next, 1-(4-(allyloxy)phenyl)ethan-1-one (2.8 g, 16 mmol, 100 mol %) was
o
stirred in o-xylene (16 mL) for 18 h at 220 C. The resulting mixture was cooled to room temperature,
diluted with EtOAc (20 mL) and concentrated in vacuo. The residue was purified by flash column
chromatography (n-hexanes/EtOAc = 6:1) to afford 2 (2.0 g, 71%) as a white solid.
o
1
1-(3-Allyl-4-hydroxyphenyl)ethan-1-one (2): 2.0 g (71%); white solid; mp = 115.8–116.4 C; H
NMR (400 MHz, CDCl3) δ 7.79–7.77 (m, 2H), 7.04 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.07–5.97 (m, 1H),
5.16–5.13 (m, 2H), 3.45 (d, J = 6.4 Hz, 2H), 2.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3,
159.4, 135.8, 131.5, 130.0, 129.3, 126.1, 116.9, 115.6, 34.7, 26.4; IR (KBr) υ 3262 (OH), 1672 (C=O) cm-
1; HRMS (orbitrap, ESI) calcd for C11H13O2 [M+H]+ 177.0910, found 177.0905.
Experimental procedure and characterization data for the synthesis of 3: To an oven-dried
round bottom flask (100 mL) charged with 2 (1.8 g, 10 mmol, 100 mol %) and THF (40 mL) was added
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 20
KOtBu (4.5 g, 40 mmol, 400 mol %) under air at room temperature. The reaction mixture was allowed to
1
2
3
o
stir for 8 h at 80 C. The resulting mixture was extracted with EtOAc (100 mL). The organic layer was
4
5
6
7
8
9
washed with saturated NH4Cl solution (2 × 60 mL), dried over MgSO4, and concentrated in vacuo. The
residue was purified by flash column chromatography (n-hexanes/EtOAc = 5:1) to afford 3 (1.7 g, 95%)
as a white solid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4-Hydroxy-3-(prop-1-en-1-yl)phenyl)ethan-1-one (3): 1.7 g (95%, E:Z = 5:1); white solid; mp
= 107.3–109.1 oC; 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.4,
2.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 16.0, 1.6 Hz, 1H), 6.35–6.26 (m, 1H), 2.59 (s, 3H),
1.90 (dd, J = 6.8, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.7, 158.0, 129.8, 129.1, 129.0,
128.4, 125.4, 124.7, 115.7, 26.4, 19.0; IR (KBr) υ 3282 (OH), 1651 (C=O) cm-1; HRMS (orbitrap, ESI)
calcd for C11H13O2 [M+H]+ 177.0910, found 177.0909.
Experimental procedure and characterization data for the synthesis of 4: To an oven-dried
round bottom flask (100 mL) charged with 3 (1.1 g, 6 mmol, 100 mol %), O-methyl hydroxylamine
hydrochloride (0.6 g, 7.2 mmol, 120 mol %) and NaOAc (0.98 g, 12 mmol, 200 mol %) was added
MeOH (12 mL) under air. The reaction mixture was allowed to stir for 4 h at room temperature. The
resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated
NH4Cl solution (2 × 30 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc = 15:1) to afford 4 (1.08 g, 87%) as a white solid.
(Z)-1-(4-Hydroxy-3-((E)-prop-1-en-1-yl)phenyl)ethan-1-one O-methyl oxime (4): 1.08 g (87%,
o
1
E:Z = 5:1); white solid; mp = 105.8–107.3 C; H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.34 (d, J =
8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 15.2 Hz, 1H), 6.27–6.18 (m, 1H), 5.83 (br s, 1H), 3.98
13
(s, 3H), 2.20 (s, 3H), 1.89 (d, J = 6.4 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 154.9, 153.5, 131.8,
10
ACS Paragon Plus Environment

Page 11 of 20
The Journal of Organic Chemistry
128.9, 125.9, 125.4, 125.2, 123.9, 115.7, 61.8, 19.0, 12.9; IR (KBr) υ 3323 (OH), 1654 (C=N), 968 (N–O)
1
2
3
cm-1; HRMS (orbitrap, ESI) calcd for C12H16NO2 [M+H]+ 206.1176, found 205.1173.
4
5
6
7
8
9
Experimental procedure and characterization data for the synthesis of 5a and 5b: To an oven-
dried round bottom flask (100 mL) charged with 4 (0.62 g, 3 mmol, 100 mol %), acetyl chloride (0.94 g,
12 mmol, 400 mol %) and N,N-diisopropylethylamine (0.94 g, 12 mmol, 400 mol %) was added CH2Cl2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
(6 mL) under air at room temperature. The reaction mixture was allowed to stir for 6 h at 60 C. The
resulting mixture was extracted with EtOAc (30 mL). The organic layer was washed with saturated
NH4Cl solution (2 × 20 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc = 20:1) to afford a separable mixture of 5a (0.53 g,
71%) and 5b (0.11 g, 14%), respectively.
4-((E)-1-(Methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl acetate (5a): 0.53 g (71%, E-
isomer); colorless oil; 1H NMR (700 MHz, CDCl3) δ 7.76 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz,
1H), 7.01 (d, J = 8.4 Hz, 1H), 6.39 (dd, J = 16.1, 2.1 Hz, 1H), 6.32–6.27 (m, 1H), 3.99 (s, 3H), 2.33 (s,
3H), 2.21 (s, 3H), 1.90 (dd, J = 7.0, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 169.3, 154.0, 148.1,
134.7, 130.5, 129.1, 125.4, 124.4, 124.2, 122.6, 62.0, 21.0, 19.0, 12.7; IR (KBr) υ 1759 (C=O), 1654
(C=N), 1197 (C–O), 963 (N–O) cm-1; HRMS (orbitrap, ESI) calcd for C14H18NO3 [M+H]+ 248.1281,
found 248.1280.
4-((E)-1-(Methoxyimino)ethyl)-2-((Z)-prop-1-enyl)phenyl acetate (5b): 0.11 g (14%, Z-isomer);
colorless oil; 1H NMR (700 MHz, CDCl3) δ 7.57 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.4, 2.1 Hz, 1H), 7.06
(d, J = 8.4 Hz, 1H), 6.29 (dd, J = 11.2, 1.4 Hz, 1H), 5.90–5.85 (m, 1H), 3.98 (s, 3H), 2.27 (s, 3H), 2.21 (s,
3H), 1.77 (dd, J = 7.0, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 169.1, 154.0, 149.1, 134.3, 130.4,
129.5, 128.2, 125.7, 124.2, 122.3, 62.1, 21.0, 14.7, 12.8; IR (KBr) υ 1759 (C=O), 1651 (C=N), 1197 (C–
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 20
O), 959 (N–O) cm-1; HRMS (orbitrap, ESI) calcd for C14H18NO3 [M+H]+ 248.1281, found 248.1280.
1
2
3
4
5
6
7
8
9
Typical procedure for the C−H acylation of 5a with aldehydes (7a–7g): To an oven-dried sealed
tube charged with 5a (98.9 mg, 0.4 mmol, 100 mol %), Pd(OAc)2 (9.0 mg, 0.04 mmol, 10 mol %) and
TBHP (0.24 mL, 1.2 mmol, 300 mol %, 5 M in decane) was added p-anisaldehyde (6a) (163.4 mg, 1.2
mmol, 300 mol %) and DCE (2 mL) under air at room temperature. The reaction mixture was allowed to
stir for 20 h at 80 oC. The reaction mixture was cooled to room temperature and extracted with EtOAc (2
× 15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (n-hexanes/EtOAc = 10:1) to afford 7a (93.1 mg) in 61% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(4-Methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl
acetate
(7a): 93.1 mg (61%); orange sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 7.58 (s,
1H), 7.12 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.45–6.34 (m, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 2.32 (s, 3H),
2.02 (s, 3H), 1.93 (d, J = 5.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.8, 169.0, 163.4, 154.3,
147.1, 138.0, 134.8, 132.3, 132.0, 130.8, 130.7, 126.4, 123.8, 123.7, 113.7, 61.8, 55.5, 21.0, 19.1, 15.2; IR
(KBr) υ 1762 (C=O), 1718 (C=O), 1658 (C=N), 1197 (C–O), 965 (N–O) cm-1; HRMS (orbitrap, ESI)
calcd for C22H24NO5 [M+H]+ 382.1649, found 382.1652.
5-(4-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl
acetate
o
1
(7b): 74.9 mg (51%); white solid; mp = 132.0–133.6 C; H NMR (700 MHz, CD3OD) δ 7.69 (s, 1H),
7.59 (d, J = 9.1 Hz, 2H), 7.10 (s, 1H), 6.80 (d, J = 9.1 Hz, 2H), 6.49–6.48 (m, 2H), 3.66 (s, 3H), 2.32 (s,
3H), 2.03 (s, 3H), 1.93 (d, J = 4.9 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 197.2, 170.7, 163.8,
155.4, 148.5, 139.4, 135.7, 133.6, 133.3, 131.9, 130.4, 127.2, 124.6, 124.5, 116.1, 61.9, 20.6, 19.0, 14.9;
IR (KBr) υ 3341 (OH), 1763 (C=O), 1716 (C=O), 1650 (C=N), 1195 (C–O), 964 (N–O) cm-1; HRMS
(orbitrap, ESI) calcd for C21H22NO5 [M+H]+ 368.1492, found 368.1493.
12
ACS Paragon Plus Environment

Page 13 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
5-(3-Methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl
acetate
1
(7c): 74.8 mg (49%); brown sticky oil; H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.34 (q, J = 1.6 Hz,
1H), 7.28 (d, J = 8.0 Hz, 1H), 7.23 (dt, J = 7.6, 1.2 Hz, 1H), 7.17 (s, 1H), 7.07 (ddd, J = 8.0, 2.8, 1.2 Hz,
1H), 6.46–6.35 (m, 2H), 3.82 (s, 3H), 3.72 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.93 (d, J = 4.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.8, 169.0, 159.7, 154.1, 147.1, 139.3, 137.6, 135.0, 132.7, 130.9,
129.4, 126.3, 124.1, 123.7, 122.5, 119.6, 113.3, 61.8, 55.6, 21.0, 19.1, 15.1; IR (KBr) υ 1769 (C=O), 1721
(C=O), 1668 (C=N), 1193 (C–O), 964 (N–O) cm-1; HRMS (orbitrap, ESI) calcd for C22H24NO5 [M+H]+
382.1649, found 382.1654.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(3-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl
acetate
o
1
(7d): 58.8 mg (40%); white solid; mp = 129.0–130.2 C; H NMR (700 MHz, CD3OD) δ 7.71 (s, 1H),
7.24 (t, J = 7.7 Hz, 1H), 7.15 (s, 1H), 7.09–7.07 (m, 2H), 6.97 (ddd, J = 7.7, 2.1, 1.4 Hz, 1H), 6.50–6.49
(m, 2H), 3.66 (s, 3H), 2.33 (s, 3H), 2.02 (s, 3H), 1.95–1.94 (m, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ
198.2, 170.7, 158.8, 155.2, 148.6, 140.6, 139.2, 135.8, 134.0, 132.1, 130.5, 126.9, 124.7, 124.6, 121.6,
121.1, 116.5, 62.0, 20.6, 19.0, 14.6; IR (KBr) υ 3385 (OH), 1768 (C=O), 1651 (C=N), 1194 (C–O), 964
(N–O) cm-1; HRMS (orbitrap, ESI) calcd for C21H22NO5 [M+H]+ 368.1492, found 368.1495.
5-(4-Hydroxy-3-methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl
acetate (7e): 54.1 mg (34%); red sticky oil; 1H NMR (400 MHz, CD3OD) δ 7.69 (s, 1H), 7.38 (d, J = 2.0
Hz, 1H), 7.16 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.50–6.49 (m, 2H), 3.85 (s,
3H), 3.69 (s, 3H), 2.32 (s, 3H), 2.03 (s, 3H), 2.03–1.92 (m, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ
197.0, 170.7, 155.7, 153.3, 149.0, 148.4, 139.2, 135.9, 133.6, 131.9, 130.7, 127.2, 126.3, 124.7, 124.5,
115.7, 113.2, 62.0, 56.3, 20.6, 19.0, 15.1; IR (KBr) υ 3404 (OH), 1762 (C=O), 1652 (C=N), 1195 (C–O),
965 (N–O) cm-1; HRMS (orbitrap, ESI) calcd for C22H24NO6 [M+H]+ 398.1598, found 398.1600.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 20
1
2
3
4
5
6
7
8
9
5-(2-Hydroxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-yl)phenyl acetate (7f):
30.9 mg (21%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 7.62 (s, 1H), 7.43 (ddd, J
= 8.8 , 7.2, 1.6 Hz, 1H), 7.24 (dd, J = 8.0, 1.6 Hz, 1H), 7.11 (s, 1H), 7.00 (dd, J = 8.4, 1.2 Hz, 1H), 6.76
(ddd, J = 9.0, 7.2, 0.8 Hz, 1H), 6.46–6.33 (m, 2H), 3.67 (s, 3H), 2.34 (s, 3H), 2.08 (s, 3H), 1.94 (d, J = 4.8
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 201.7, 168.9, 162.4, 152.8, 147.3, 136.5, 136.0, 133.8,
132.6, 132.3, 131.0, 126.0, 123.6, 123.2, 120.5, 118.9, 118.0, 61.9, 21.0, 19.1, 14.1; IR (KBr) υ 3401
(OH), 1765 (C=O), 1630 (C=N), 1192 (C–O), 965 (N–O) cm-1; HRMS (orbitrap, ESI) calcd for
C21H22NO5 [M+H]+ 368.1492, found 368.1508.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-(2,4-Dihydroxy-3-methoxybenzoyl)-4-((E)-1-(methoxyimino)ethyl)-2-((E)-prop-1-en-1-
yl)phenyl acetate (7g): 29.8 mg (18%); yellow sticky solid; 1H NMR (700 MHz, CD3OD) δ 7.72 (s, 1H),
7.11 (s, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.8 Hz, 2H), 6.31 (d, J = 9.1 Hz, 1H), 3.86 (s, 3H), 3.67
(s, 3H), 2.33 (s, 3H), 2.09 (s, 3H), 1.94–1.93 (m, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 201.9, 170.7,
158.5, 158.3, 154.7, 148.6, 138.0, 136.1, 134.9, 133.7, 132.0, 130.0, 127.0, 124.5, 124.1, 115.7, 108.9,
62.0, 60.8, 20.6, 19.0, 14.3; IR (KBr) υ 3396 (OH), 1754 (C=O), 1614 (C=N), 1191 (C–O), 963 (N–O)
cm-1; HRMS (orbitrap, ESI) calcd for C22H24NO7 [M+H]+ 414.1547, found 414.1554.
Typical procedure for the synthesis of penchinone A derivatives via acidic hydrolysis (8a–8g): To an
oven-dried sealed tube charged with 7a (76.3 mg, 0.2 mmol, 100 mol %) was added 0.5 M HCl (1 mL)
and MeOH/acetone (1 mL, 1:1) under air at room temperature. The reaction mixture was allowed to stir
for 4 h at 80 oC. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3
solution (1 mL) to make pH 7 of reaction mixture and then extracted with EtOAc (2 × 10 mL). The
organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography (n-hexanes/EtOAc = 3:1) to afford 8a (32.9 mg) in 53% yield.
14
ACS Paragon Plus Environment

Page 15 of 20
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(E)-1-(4-Hydroxy-2-(4-methoxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8a): 32.9 mg
o
1
(53%); white solid; mp = 177.2–178.6 C; H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.65 (d, J = 8.8
Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.72 (dd, J = 16.0, 1.6 Hz, 1H), 6.68 (s, 1H), 6.55–6.46 (m, 1H), 3.84 (s,
3H), 2.47 (s, 3H), 1.94 (dd, J = 6.4, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.1, 199.0,
165.2, 159.4, 142.5, 132.5, 131.3, 130.5, 129.6, 129.2, 127.1, 125.9, 115.9, 114.7, 56.0, 26.8, 19.1; IR
(KBr) υ 3295 (OH), 1671 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C19H19O4 [M+H]+ 311.1278,
found 311.1290.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-1-(4-Hydroxy-2-(4-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8b): 42.2 mg
(71%); white solid; mp = 233.1–234.9 oC; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.57 (d, J = 8.8,
2H), 6.78 (d, J = 8.8 Hz, 2H), 6.71 (dd, J = 16.0, 1.6 Hz, 1H), 6.67 (s, 1H), 6.54–6.45 (m, 1H), 2.47 (s,
3H), 1.94 (dd, J = 6.8, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.2, 199.0, 163.8, 159.5,
142.7, 132.9, 130.5, 130.1, 129.5, 129.1, 127.1, 126.0, 116.1, 116.0, 26.9, 19.1; IR (KBr) υ 3289 (OH),
1676 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C18H17O4 [M+H]+ 297.1121, found 297.1122.
(E)-1-(4-Hydroxy-2-(3-methoxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8c): 24.9 mg
(40%); brown sticky oil; 1H NMR (700 MHz, CD3OD) δ 8.04 (s, 1H), 7.31–7.28 (m, 2H), 7.12–7.10 (m,
2H), 6.72 (dd, J = 16.1, 1.4 Hz, 1H), 6.71 (s, 1H), 6.54–6.49 (m, 1H), 3.80 (s, 3H), 2.46 (s, 3H), 1.94 (dd,
J = 6.3, 2.1 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 199.6, 199.0, 161.2, 159.7, 142.3, 139.9, 130.5,
129.6, 129.3, 127.3, 125.9 (two carbon overlap), 122.9, 120.1, 116.0, 114.1, 55.8, 26.6, 19.1; IR (KBr) υ
3274 (OH), 1670 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C19H19O4 [M+H]+ 311.1278, found
311.1289.
(E)-1-(4-Hydroxy-2-(3-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8d): 26.6 mg
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 20
o
1
(45%); white solid; mp = 215.0–216.5 C; H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.22 (t, J = 7.6
Hz, 1H), 7.12–7.08 (m, 2H), 6.96 (ddd, J = 7.8, 2.8, 1.2 Hz, 1H), 6.74–6.70 (m, 1H), 6.70 (s, 1H), 6.55–
6.46 (m, 1H), 2.47 (s, 3H), 1.94 (dd, J = 6.8, 2.0 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 199.9,
199.1, 159.7, 158.7, 142.5, 139.8, 130.5, 130.4, 129.6, 129.2, 127.3, 126.0, 121.5, 121.1, 116.3, 116.0,
26.6, 19.1; IR (KBr) υ 3346 (OH), 1668 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C18H17O4 [M+H]+
297.1121, found 297.1129.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-1-(4-Hydroxy-2-(4-hydroxy-3-methoxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8e):
35.9 mg (55%); white solid; mp = 168.4–169.9 oC; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.46 (d,
J = 2.0 Hz, 1H), 7.01 (dd, J = 8.4, 2.0 Hz, 1H), 6.76–6.70 (m, 2H), 6.69 (s, 1H), 6.54–6.45 (m, 1H), 3.87
13
(s, 3H), 2.47 (s, 3H), 1.94 (dd, J = 6.8, 1.6 Hz, 3H); C{1H} NMR (100 MHz, CD3OD) δ 199.2, 198.9,
159.4, 153.3, 149.0, 142.5, 130.5, 130.4, 129.7, 129.1, 127.1, 126.3, 126.0, 116.1, 115.5, 112.3, 56.3, 26.9,
19.1; IR (KBr) υ 3311 (OH), 1650 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C19H19O5 [M+H]+
327.1227, found 327.1239.
(E)-1-(4-Hydroxy-2-(2-hydroxybenzoyl)-5-(prop-1-en-1-yl)phenyl)ethan-1-one (8f): 36.3 mg
(61%); white solid; mp = 100.7–102.6 oC; 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.46 (ddd, J = 8.6,
6.8, 1.6 Hz, 1H), 7.07 (dd, J = 7.6, 1.6 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.79–6.73 (m, 2H), 6.72 (s,
1H), 6.58–6.49 (m, 1H), 2.51 (s, 3H), 1.96 (dd, J = 6.4, 1.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD)
δ 205.2, 198.7, 163.3, 160.1, 140.7, 136.9, 133.1, 130.7, 129.3, 128.7, 127.5, 125.9, 121.5, 119.9, 118.7,
115.8, 26.5, 19.1; IR (KBr) υ 3276 (OH), 1671 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C18H17O4
[M+H]+ 297.1121, found 297.1133.
(E)-1-(2-(2,4-Dihydroxy-3-methoxybenzoyl)-4-hydroxy-5-(prop-1-en-1-yl)phenyl)ethan-1-one
o
1
(8g): 41.2 mg (60%); white solid; mp = 111.2–113.9 C; H NMR (700 MHz, CD3OD) δ 8.07 (s, 1H),
16
ACS Paragon Plus Environment

Page 17 of 20
The Journal of Organic Chemistry
6.74–6.72 (m, 2H), 6.70 (s, 1H), 6.55–6.50 (m, 1H), 6.29 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H), 2.52 (s, 3H),
1.96 (dd, J = 6.3, 1.4 Hz, 3H); 13C{1H} NMR (175 MHz, CD3OD) δ 203.8, 198.9, 159.5, 158.5, 158.3,
140.7, 136.0, 130.6, 129.9, 129.3, 128.9, 127.3, 125.9, 115.9, 115.4, 108.8, 60.8, 26.8, 19.1; IR (KBr) υ
3279 (OH), 1651 (C=O) cm-1; HRMS (orbitrap, ESI) calcd for C19H19O6 [M+H]+ 343.1176, found
343.1179.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cell culture and cell viability assay: Murine RAW264.7 macrophage cell line was obtained from
American Type Culture Collection (ATCC) and cultured in Dulbecco’s modified Eagle’s medium
o
(DMEM) supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin at 37 C in a
humidified atmosphere containing 5% CO2. Cell viability was determined by 3-[4,5-dimethylthiazol-2-
yl]-2,5 diphenyl tetrazolium bromide (MTT) reduction assay. In brief, RAW264.7 cells were preincubated
overnight in 96-well plates at a density of 1 х 104 cells per well. After 24 h, cells were treated with
various concentrations (0.1, 1, 10 µg/mL) of synthetic compounds for another 24 h. The mediums then
were removed, and MTT was then added to each well at a final concentration of 0.5 mg/mL. The cells
o
were incubated for 4 h at 37 C, supernatants were removed, and dimethyl sulfoxide was added to each
well. The optical density was measured at 540 nm using a microplate reader.
Determination of nitric oxide: RAW264.7 cells were treated with compounds for 2 h, followed by
the addition with LPS (1 µg/mL) for an additional 24 h. NO concentration in the culture supernatants was
measured using a previously described assay system. The NO levels were used as an indicator of the
amount of NO production. One hundred µL of Griess regent (1% sulfanilamide in 5% phosphoric acid,
1% α-naphthylamide in H2O) in a 96-well plate, incubated at room temperature for 15 min, and then
measured at 550 nm using a Molecular Device microplate reader.
Cytokine determination by ELISA. RAW264.7 cells were pretreated with compounds, followed by
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 20
the addition of LPS (1 µg/mL) to the cultures for 24 h. The concentration of the TNF-α and IL-6 in each
1
2
3
sample was determined using DuoSet Elisa kit according to the manufacturer`s instructions.
4
5
6
7
8
9
Statistical Analysis. Each result is reported as means S.E.M. All experiments were performed at
least three times. For comparisons between two groups, the Student’s t test (SigmaPlot) was used. Multi-
group comparisons of mean values were analyzed by one-way ANOVA (GraphPad program).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgment
This research was supported by research grant commission of Gyeonggi Biocenter funded by
Gyeonggi-do, Republic of Korea.
Supporting Information Available: Cell viability and dose-dependent inhibition data of
compounds 7a–7g and 8a–8g, and 1H and 13C NMR copies of all products. This material is available free
of charge via the internet at http://pubs.acs.org.
References and notes
1. For selected reviews, see: (a) Umezawa, T. Phytochem. Rev. 2003, 2, 371. (b) Landete, J. M. Food Res.
Int. 2012, 46, 410. (c) Kassuya, C. A. L.; Leite, D. F. P.; de Melo, L. V.; Rehder, V. L. G.; Calixto, J. B.
Planta Med. 2005, 71, 721.
2. For selected reviews, see: (a) Saleem, M.; Kim, H. J.; Ali, M. S.; Lee, Y. S. Nat. Prod. Rep. 2005, 22,
696. (b) Pan, J. Y.; Chen, S. L.; Yang, M. H.; Wu, J.; Sinkkonen, J.; Zou, K. Nat. Prod. Rep. 2009, 26,
1251.
3. He, Y.-C.; Peng, C.; Xie, X.-F.; Chen, M.-H.; Li, X.-N.; Li, M.-T.; Zhou, Q.-M.; Guo, L.; Xiong, L.
RSC Adv. 2015, 5, 76788.
4. (a) Lu, Q.; Jiang, M. H.; Jiang, J. G.; Zhang, R. F.; Zhang, M. W. J. Agric. Food Chem. 2012, 60, 11097.
18
ACS Paragon Plus Environment

Page 19 of 20
The Journal of Organic Chemistry
(b) He, Y. C.; Zou, Y.; Peng, C.; Liu, J. L.; He, C. J.; Guo, L.; Xie, X. F.; Xiong, L. Fitoterapia 2015,
100, 7.
1
2
3
4
5. (a) Surburg, H.; Panten, J. Common Fragrance and Flavor Materials, 5th ed.; Wiley-VCH: Weinheim,
Germany, 2006. (b) Deng, Y.; Chin, Y.-W.; Chai, H.; Keller,W. J.; Kinghorn, A. D. J. Nat. Prod. 2007,
70, 2049. (c) Romins, K. R.; Freeman, G. A.; Schaller, L. T.; Cowan, J. R.; Gonzales, S. S.; Tidwell, J.
H.; Andrews, C. W.; Stammers, D. K.; Hazen, R. J.; Ferris, R. G.; Short, S. A.; Chan, J. H.; Boone, L. R.
J. Med. Chem. 2006, 49, 727.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6. (a) Sharma, S.; Mishra, N. K.; Shin, Y.; Kim, I. S. Curr. Org. Chem. 2016, 20, 471. (b) Hummel, J. R.;
Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117, 9163.
7. (a) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2011,
13, 4390. (b) Sharma, S.; Park, E.; Park, J.; Kim, I. S. Org. Lett. 2012, 14, 906.
8. For selected examples, see (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009, 11,
3120. (b) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926. (c) Shin, Y.;
Sharma, S.; Mishra, N. K.; Han, S.; Park, J.; Oh, H.; Ha, J.; Yoo, H.; Jung, Y. H.; Kim, I. S. Adv. Synth.
Catal. 2015, 357, 594. (d) Sharma, S.; Kim, M.; Park, J.; Kim, M.; Kwak, J. H.; Jung, Y. H.; Oh, J. S.;
Lee, Y.; Kim, I. S. Eur. J. Org. Chem. 2013, 6656. (e) Han, S.; Sharma, S.; Park, J.; Kim, M.; Shin, Y.;
Mishra, N. K.; Bae, J. J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2014, 79, 275. (f) Guin, S.;
Rout, S. K.; Banerjee, A.; Nandi, S.; Patel, B. K. Org. Lett. 2012, 14, 5294.
9. (a) Jeon, M.; Mishra, N. K.; De, U.; Sharma, S.; Oh, Y.; Choi, M.; Jo, H.; Sachan, R.; Kim, H. S.; Kim,
I. S. J. Org. Chem. 2016, 81, 9878. (b) Han, S. H.; Kim, S.; De, U.; Mishra, N. K.; Park, J.; Sharma, S.;
Kwak, J. H.; Han, S.; Kim, H. S.; Kim, I. S. J. Org. Chem. 2016, 81, 12416. (c) Sharma, S.; Oh, Y.;
Mishra, N. K.; De, U.; Jo, H.; Sachan, R.; Kim, H. S.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2017, 82,
3359.
10. (a) Huang, G.-J.; Reddy, M. V. B.; Kuo, P.-C.; Huang, C.-H.; Shih, H.-C.; Lee, E.-J.; Yang, M.-L.; Leu,
Y.-L.; Wu, T.-S. Eur. J. Med. Chem. 2012, 48, 371. (b) Xu, X.; Yin, P.; Wan, C.; Chong, X.; Liu, M.;
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 20
Cheng, P.; Chen, J.; Liu, F.; Xu, J. Inflammation 2014, 37, 956.
1
2
3
11. (a) Quintans, J. Immunol. Cell Biol. 1994, 72, 262. (b) Duncan, A. J.; Heales, S. J. Mol. Aspects Med.
4
5
2005, 26, 67.
6
7
8
9
12. (a) Oh, Y.-C.; Jeong, Y. H.; Cho, W.-K.; Ha, J.-H.; Gu, M. J.; Ma, J. Y. Int. J. Mol. Sci. 2015, 16, 1232.
(b) Li, Q.; Dong, D.-D.; Huang, Q.-P.; Li, J.; Du, Y.-Y.; Li, B.; Li, H.-Q.; Huyan, T. Pharm. Biol. 2017,
55, 799.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
ACS Paragon Plus Environment