Total synthesis and anti-inflammatory evaluation of violacin A and its analogues

Article abstract of DOI:10.1016/j.bioorg.2019.103420

A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A as well as the preparation of thirty analogues of this lead from commercially available orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts acylation, the regioselective etherification and esterification of phenolic hydroxyl groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A. The deprotection reaction with Pd-catalytic was involved to avoid the elimination of the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO) production using lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives 11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for anti-inflammatory activities of violacin A derivatives. Additionally, Western blot results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines releases correlated with the suppression of NF-κB signaling pathway.

Full text of DOI:10.1016/j.bioorg.2019.103420

Journal Pre-proofs
Total synthesis and anti-inflammatory evaluation of violacin A and its ana-
logues
Qingyin Liu, Yu Mu, Qi An, Jiali Xun, Jian Ma, Wenxi Wu, Minjuan Xu, Jun
Xu, Li Han, Xueshi Huang
PII:
S0045-2068(19)31211-8
DOI:
https://doi.org/10.1016/j.bioorg.2019.103420
YBIOO 103420
Reference:
To appear in:
Bioorganic Chemistry
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Accepted Date:
29 July 2019
1 November 2019
Please cite this article as: Q. Liu, Y. Mu, Q. An, J. Xun, J. Ma, W. Wu, M. Xu, J. Xu, L. Han, X. Huang, Total
synthesis and anti-inflammatory evaluation of violacin A and its analogues, Bioorganic Chemistry (2019), doi:
https://doi.org/10.1016/j.bioorg.2019.103420
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Total synthesis and anti-inflammatory evaluation of violacin A and
its analogues
Qingyin Liua, Yu Mua, Qi Ana, Jiali Xuna, Jian Maa, Wenxi Wua, Minjuan Xub, Jun
c
a,
a,


Xu , Li Han , Xueshi Huang
aInstitute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang 110819, P. R.
China
bKey Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai
200240, P. R. China
cState Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University,
Shanghai 200240, P. R. China
*Corresponding authors
1

E-mail addresses: hanli@mail.neu.edu.cn (L. Han) and huangxs@mail.neu.edu.cn (X. Huang).
ABSTRACT
A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A
as well as the preparation of thirty analogues of this lead from commercially available
orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts
acylation, the regioselective etherification and esterification of phenolic hydroxyl
groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A.
The deprotection reaction with Pd-catalytic was involved to avoid the elimination of
the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for
anti-inflammatory activity against nitric oxide (NO) production using
lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives
11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than
that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for
anti-inflammatory activities of violacin A derivatives. Additionally, Western blot
results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines
releases correlated with the suppression of NF-B signaling pathway.
Keywords: Violacin A; Total synthesis; NF-B; Anti-inflammatory activity.
2

1. Introduction
Currently, nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-cytokine
biologics are available for inflammation treatment, but their side effects or excessive
costs frequently limit their use [1,2]. In the pursuit of safer, more economics and more
effective compounds of less side effects, the natural-occurring products have been a
vital source of therapeutics targeting inflammation.
Chromanones and chromones were widely distributed in nature and exhibited broad
spectrum of biological activities such as anti-inflammatory, antioxidant, and antitumor
activities [3-5], and had being considered as privileged scaffolds in drug discovery.
Chromanones usually possessed a chroman-4-one skeleton and were distinct from
chromones with a C2-C3 single bond. Along with their potent bioactivities and unique
structures, the total synthesis of these scaffolds have attracted interest from the synthetic
community. However, the total synthesis strategy for the chromanone with a hemiacetal
hydroxyl at C2 was rarely reported [6-9], notably the hydroxyl was easily eliminated to
form a conjugated double bond with the carbonyl group at C4 under acidic conditions.
Faced with the intriguing question and the natural scarcity, we embarked on a program
directed toward the total synthesis of violacin A (Fig. 1), which was first identified from
a fermentation broth of Streptomyces violaceoruber obtained from healthy adult Equus
burchelli (zebra) and presented remarkable anti-inflammatory effect in our previous
study [10]. In this study, we described an efficient synthesis of violacin A involving the
construction of basic skeleton of target molecule by NaH-promoted Baker-
Venkatamaran rearrangement, followed by Pd-catalyzed deprotection. Simultaneously,
as scaffolds for development of novel anti-inflammatory drugs, we became interested
in preparing derivatives with etherification at C7-OH, alkyl and hydroxyl substituents
at C2 or acetalization at C2′. So we designed and synthesized twenty-five new and five
known derivatives of violacin A based on its total synthetic route in the search for more
suitable candidates for clinical study. Subsequently, the inhibitory effects of target
3

compounds and intermediates on nitric oxide (NO) release were evaluated using
lipopolysaccharide (LPS)-induced Raw264.7 macrophage and anti-inflammatory
mechanism was also investigated by using derivative 17d as a representative.
Fig. 1. The structure of violacin A.
2. Results and discussion
2.1. Chemistry
Retrosynthetic analysis for the synthesis of violacin A is shown in Scheme 1. The
ketone 8 serves as a pretarget molecule, which results from Baker-Venkatamaran
rearrangement of 7. Intermediate 7 in turn could be assembled from ortho-hydroxy
acetophenone derivative 6 and acid 3. Aromatic building block 6 is derived from
commercially available orcinol 4 through Friedel-Crafts acylation reaction and
followed by regioselective O-etherification. Acid building block 3 could be obtained
from the hydrolysis of fructone, which could be prepared from regioselectivity
ketalization of carbonyls of 1.
Scheme 1. Retrosynthetic analysis of 1.
The synthesis was initiated with the synthesis of 2,4-dihydroxy-6-methyl-
acetophenone 5 from commercially available orcinol (4) following a literature protocol
[11]. And the yield was increased to 82%, when the 3A molecular sieve was added to
the reaction system, which was possibly attributed to water absorption and the ease of
4

diffusion of the reactants and products [12]. Subsequently, 5 undergoes a condensation
reaction with 1 in one-pot, in order to efficiently and quickly achieve the target
molecule violacin A, but it was unsuccessful, probably due to the self-condensation of
ethyl acetate 1 under the action of sodium hydride (Scheme 2).
Scheme 2. Synthetic trials towards violacin A. Reagents and conditions: (a) AcOH, BF3-Et2O, 3A
Molecular sieve, 90 oC, 18 h; (b) Ethyl acetoacetate, NaH, THF, reflux, 3.5 h.
Therefore, we had to revise the synthesis strategy. The dihydric phenol 5 and 1 were
also chosen as the starting materials for the new synthesis approach. Etherification of 5
with iodomethane in refluxing acetone in the presence of potassium carbonate achieved
the selective methylation of the less encumbered phenolic group to provide the methyl
ether 9a [13,14]. At the same time, the carbonyl group of β-keto ester 1 was protected
using standard methodology providing ketal 2. Further ester hydrolysis under basic
conditions gave compound 3 [15,16]. Then, 10a was obtained by connecting building
blocks 9a and 3 by esterification reaction under Steglich conditions. Treatment of a dry
THF solution of ester 10a with KOtBu or NaH as a base smoothly afforded the key
hemiacetal 11a (Baker-Venkatamaran rearrangement), and in terms of yield, the use of
NaH as the base (92%) was significantly better than KOtBu (60%) (Scheme 3).
5

Scheme 3. Synthesis of intermediate 11a. Reagents and conditions: (a) p-TSA, ethylene glycol,
benzene, refluxe, 20 h; (b) 2 N KOH(aq.), ethanol, rt, 4 h; (c) MeI, K2CO3, acetone, reflux, 5 h; (d) Comp.
3, DCC, DMAP, DCM, rt, 20 h; (e) NaH, THF, reflux, 3.5 h.
Unfortunately, this approach to obtain violacin A from hemiacetal 11a was thwarted in
the progress of removals of the O-methyl and ketal groups (Table 1) by several attempts
with relatively mild reaction conditions [17-19]. Invariably, deprotection was
accompanied by elimination of hemiacetal hydroxyl at C2 position.
Table 1. Attempts at deprotection of 11a.
Yield (%)a
entry
reagents
solvent
T (oC) time (h)
12a
13a
14 [20]
1
2
3
4
AlCl3
AlCl3
AlCl3
BBr3
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
0
6
15
15
8
0
0
0
0
0
0
0
r.t.
r.t.
-60
30
35
40
0
32
6

5
6
7
8
BBr3
BBr3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
r.t.
-20
0
8
28
0
45
0
0
85
0
18
0.5
0.5
Me3SiI
Me3SiI
30
10
50
82
0
aIsolated yields.
Therefore, we tried to protect the hydroxyl at C2 with TBS. Regrettably, the failure of
this approach was announced at the time of obtaining 16 (Scheme 4).
Scheme 4. Synthesis of compound 16. Reagents and conditions: (a) TBDMSCl, im, DCM, rt, 10 h.
To avoid this obstacle, recourse was taken to the O-benzylated 9b, which was
obtained with a less selectively than the corresponding O-methylation from treating the
dihydric phenol 5 with benzyl chloride, potassium carbonate and sodium iodide in
refluxing acetonitrile. Then, the 9b further transformed into the key intermediate 11b
by the same protocol as that used to synthesize 9a from 11a. Afterwards, in order to
keep away from the elimination of the hemiacetal hydroxyl at C2 of 11b, a soft Lewis
acid PdCl2(CH3CN)2 was used to remove the ketal protecting group [21]. Thus, on
o
treatment with a catalytic amount of the palladium catalyst at 0 C, in acetone and
darkness, 11b easily underwent ketal hydrolysis to give 17b. Finally, hydrogenolysis
[22] of 17b proceeded prospectively to obtain a nearly quantitative yield of violacin A.
Remarkably, violacin A was also produced from 18, which was obtained by
hydrogenation of 11b or NaH-promoted cyclization of 19 from esterification of
dihydric phenol 5 with acid 3. At this point, the quantity of catalyst PdCl2(CH3CN)2
was increased to 0.3 eq. over the previous 0.2 eq. (Scheme 5).
7

Scheme 5. Total synthesis of violacin A. Reagents and conditions: (a) BnCl, K2CO3, NaI, CH3CN, reflux,
1.5 h; (b) Comp. 3, DCC, DMAP, DCM, rt, 20 h; (c) NaH, THF, reflux, 3.5 h; (d) PdCl2(CH3CN)2,
acetone, 0 oC; (e) H2, Pd-C, MeOH, rt, overnight; (f) Comp. 3, DCC, DMAP, DCM, rt, 20 h; (g) NaH,
THF, reflux, 3.5 h; (h) H2, Pd-C, MeOH, rt, overnight; (i) PdCl2(CH3CN)2, acetone, 0 oC.
With the total synthetic approach of violacin A, various 7-methyl or substituted
benzyl derivatives 11a-11g and 17a-17g were prepared in similar yields. To construct
other structural analogues, we performed the Me3SiI-mediated hydrolysis of all
compounds 11a-11g. Hemiacetal hydroxyl and ketal moieties were readily removed by
using Me3SiI [18] in dichloromethane at 0oC to furnish the corresponding products 13a-
13g. At the same time, 12a-12g were also obtained from 11a-11g by treating with
methanolic K2CO3 in good yields (Scheme 6).
8

Scheme 6. Synthesis of violacin A derivatives. Reagents and conditions: (a) K2CO3, NaI, Alkyl
chloride/bromide/iodide, reflux; (b) Comp. 3, DCC, DMAP, DCM, rt, 20 h; (c) NaH, THF, reflux, 3.5 h;
(d) PdCl2(CH3CN)2, acetone, 0 oC; (e) Me3SiI, DCM, 0 oC, 20 min; (f) K2CO3, MeOH, rt, 24 h.
2.2. Effects of compounds on the production of NO in LPS-induced Raw 264.7 cells
Inflammation has been known as an early response of host against pathogenic
challenge. In this process, activated inflammatory cells can secrete increased amounts
of NO [23]. Macrophages play a key role in the progress of inflammation, and
measuring the production of NO in LPS-stimulated Raw 264.7 cells are widely used for
evaluating the anti-inflammatory effects of molecules. Since cytotoxicity of the tested
compound would inhibit the cell viability to produce false positive results in the process
9

of anti-inflammatory evaluation, the MTT assay was firstly carried out. The results
showed the double bond at C-2 could increase the cytotoxicity of target compounds
(12b-d, 12f and 13b-f), while C-7 methoxyl or 2,4-difluorobenzyloxyl possibly
decreased the cytotoxicity (12a, 12g, 13a, and 13g) (Fig. 2A). Then, the anti-
inflammatory activities of violacin A and synthetic derivatives (11a-f, 12a, 12e, 12g,
13g, 14, 17a-b, 17d-g) without cytotoxcities were evaluated by Griess method using
LPS-stimulated Raw264.7 cells. A commercial regent, minocycline, was selected as a
positive control. As shown in figure 2B, compounds 11b, 11d-f, 12e, 12g, 13g, 17b,
and 17d-g were found to display potent inhibitory activities against NO production,
stronger than those of minocycline and violacin A. The further investigation also
demonstrated that the anti-inflammatory effect of tested compounds were dose-
dependent (Fig. 2C). In particular, the results indicated that benzyloxyl, especially
halogeno-benzyloxyl, could dramatically improve the anti-inflammatory effect of
synthetized molecule.
Fig. 2. The cell viability and effect of synthetic compounds on the production of nitric oxide
(NO) in lipopolysaccharide (LPS)-induced RAW264.7 cells. The cytotoxicity of synthetic
compounds (33 μM) was measured by MTT assay (A). The production of NO was determined
by Griess method. The cells were treated, respectively, with the 33 μM of synthetic compounds
for 2 h, and then stimulated with LPS (1 µg/mL) for 24 h, then the culture medium was collected
to detect NO release. The inhibition of NO production calculated through OD values (
B). Cells
were respectively pretreated with the different concentrations of 11d 11f 17d 17f, violacin A,
,
,
,
and Mino (0, 3.3, 10, and 33 µM) for 2 h and then stimulated with or without LPS (1 µg/mL) for
10

24 h (C). The data represent the means ± SD values of three independent experiments.
2.3. Compound 17d suppressed release of IL-6, IL-1β and TNF-α in LPS-induced
Raw264.7 cells
The release of pro-inflammatory cytokines, including factor-α (TNF-α), interleukin-
1β (IL-1β), and interleukin-6 (IL-6) plays an important role in inducing inflammation
[25]. The effect of the halogeno-benzyloxyl violacin compound 17d on the secretion of
pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in LPS-stimulated Raw264.7 cells
were further investigated through Elisa assay. The release levels of TNF-α, IL-1β, and
IL-6 in model cells were dramatically inhibited in a dose-dependent manner after
treatment with 17d. The results indicated that halogeno-benzyloxyl derivative 17d
could reduce the release of pro-inflammatory cytokines to present anti-inflammatory
potential.
Fig. 3. Effect of 17d on LPS-induced release of IL-6, IL-1β, and TNF- in RAW 264.7 cells.
The cells were treated with different concentrations of 17d (0~33 μM) for 2 h, and then stimulated
with or without LPS (1 μg/mL) for 12 h. The culture medium was collected to detect the
production of TNF-α (A), IL-6 (B) and IL-1 (C) were measured using Elisa kits. Minocycline
(MINO) was used as the positive control. The results show mean ± SD values of triplicate tests
(### p < 0.001 vs. control group; *** p < 0.001, vs. LPS group).
2.4. Compounds 17d inhibits the activation of NF-κB signaling pathway in LPS-induced
Raw264.7 cells
A number of studies have shown that nuclear factor-B (NF-B) signaling pathway
plays a key role in inflammatory responses. Upon activation, phosphorylation,
ubiquitination and degradation of NF-B p65 inhibitor IKB- results in p65 release and
translocation to nucleus [26]. The phosphorylation of p65 also involved in the process
of signaling transduction pathway activation [27]. In the current study, the effect of 17d
on the NF-B activation was further investigated. The results revealed that 17d could
11

markedly inhibit the phosphorylation of IB- and p65, and increase the accumulation
of IB- in the LPS-stimulated cells. The detection of the protein levels of p65 in the
cytosol and nucleus of cells indicated that 17d attenuated the translocation of p65 from
the cytosol to the nucleus. These events demonstrated that 17d effectively inhibited the
NF-B activation to suppress the inflammatory effect in LPS-stimulated cells.
Fig. 4. Effect of 17d on LPS-induced activation of NF-κB pathway in RAW264.7 cells. Cells were
pretreated with various concentrations of concentrations (0~33 uM) of 17d or MINO (uM) for 2 h and
then stimulated with or without LPS (1 μg/mL) for 30 min. The protein levels of phospho-p65, phospho-
IκB-α, and IκB-α were analyzed using Western blot (A-D). Cytosolic (E) and nuclear (F) protein were
prepared and the expression of p65 were determined by Western blot. Data are expressed as the mean ±
SD values of three independent experiments. ###, p < 0.001 was compared to control. *, p < 0.05, **, p
< 0.01, ***, p < 0.001 compared to LPS.
3. Conclusions
In conclusion, we described the concise total synthesis of violacin A and its
analogues via the Friedel-Crafts acylation, regioselective etherification of phenolic
hydroxyl, Baker-Venkatamaran rearrangement, and deprotection reaction with Pd-
catalytic etc. from commercially available orcinol. In addition, violacin A and synthetic
12

derivatives without cytotoxicities were tested for anti-inflammatory activity using
lipopolysaccharide (LPS)-induced Raw264.7 cells. Generally, a range of violacin A
derivatives potently inhibited NO production, compared to minocycline as a positive
control. Notably, derivatives 11b, 11d, 11f, 12e, 12g, 13g, and 17d-g were found to
exhibit anti-inflammatory activity stronger than that of violacin A. The NO inhibition
effect indicated that substitutions at the C7 position of the chromanone moiety,
particularly with the halogeno-benzyloxy substituent, were more favourable for NO
release inhibition. The halogeno-benzyloxy derivative 17d showed a stronger inhibition
on the production of production of NO, IL-1, IL-6, and TNF- via inhibition of the
signaling pathways of NF-B in Raw 264.7 cells. Therefore, these compounds based
on natural product violacin A may be valuable leads for the development of new anti-
inflammatory drugs.
4. Experimental section
4.1. Chemistry
Reactions requiring anhydrous conditions were carried out under a nitrogen
atmosphere. THF were freshly distilled from sodium/benzophenone ketyl and
transferred via syringe. Dichloromethane was freshly distilled from P2O5.
Commercially available reagents were used as received. IR spectra were recorded with
a Bruker Tensor 27 FT-IR spectrometer (film). 1D NMR spectra were collected on a
Bruker AV-600 spectrometer. The solvent used for NMR spectroscopy was deuteriated
chloroform or dimethyl sulfoxide, using tetramethylsilane as the internal reference.
Chemical shifts are given in parts per million, and J values are given in Hertz.
HRESIMS were measured with an Agilent G6230 TOF mass spectrometer. All
chromatographic manipulations used silica gel (100-200 mesh, 200-300 mesh, Qingdao
Marine Chemical Ltd., Qingdao, China) as the adsorbent. Reactions were monitored
using thin layer chromatography (TLC) on aluminum. TLC plates were visualized by
UV radiation at a wavelength of 254 nm or stained by exposure to an ethanolic solution
of concentrated sulfuric acid and anisaldehyde, followed by charring where appropriate.
13

The following abbreviations are used to designate signal multiplicity: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad.
4.2. Synthetic methods of all compounds
4.2.1. Synthesis of compound 5
To a solution of orcinol 4 (5.0 g, 40.3 mmol) and 3A molecular sieve in acetic acid
(23.1 mL, 403 mmol) was added BF3-Et2O (7.62 mL, 60.4 mmol) by dropwise at room
o
temperature. After stirring for 18 h at 90 C, the reaction mixture was quenched by
addition of saturated ammonium chloride solution. The acetic acid was removed by
distillation under reduced pressure, the residue was dissolved in EtOAc and washed
with saturated sodium carbonate solution, water and brine. The organic layer was dried
over anhydrous Na2SO4, and concentrated in vacuo. Purification of the crude product
on silica gel column chromatography (EtOAc/petroleum ether = 1:6) afforded 5 (5.0 g,
75%) as a colorless solid; 1H NMR (600 MHz, CDCl3) δ 13.40 (s, 1H), 6.19 (d, J = 2.6
Hz, 1H), 6.17 (d, J = 2.6 Hz, 1H), 5.62 (s, 1H), 2.56 (s, 3H), 2.49 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 204.2, 166.8, 160.9, 142.9, 115.6, 111.9, 101.8, 33.1, 25.2.
4.2.2. General procedure for the synthesis of compounds 9b-9g
Benzyl bromide or benzyl chloride with different substituents was added to a stirred
suspension of anhydrous potassium carbonate (3.0 eq.) and sodium iodide (0.2 eq.) in
acetonitrile, containing 5, and the mixture was refluxed for 1.5 h. After filtration and
evaporation, dichloromethane was added, and the organic phase was washed with water
and brine, dried over anhydrous Na2SO4, and evaporated under vacuum. The residue
was purified by silica gel column chromatography EtOAc/Petroleum ether (1/12) as
eluents.
4.2.2.1. 1-(4-(benzyloxy)-2-hydroxy-6-methylphenyl)ethan-1-one (9b). Reagent: benzyl
chloride. Followed the above procedure gave 9b as a colorless oil. Yield 54%; 1H NMR
(600 MHz, CDCl3) δ 13.54 (s, 1H), 7.40 (m, 4H), 7.34 (m, 1H), 6.38 (d, J = 2.7 Hz,
1H), 6.37 (d, J = 2.7 Hz, 1H), 5.06 (s, 2H), 2.62 (s, 3H), 2.56 (s, 3H); 13C NMR (150
14

MHz, CDCl3) δ 204.0, 167.1, 163.5, 141.9, 136.0, 128.7 (2×C), 128.3, 127.5 (2×C),
115.3, 112.4, 100.0, 70.0, 33.1, 25.2.
4.2.2.2. 1-(2-hydroxy-6-methyl-4-((4-methylbenzyl)oxy)phenyl)ethan-1-one (9c).
Reagent: p-methylbenzyl chloride. Followed the above procedure gave 9c as a white
solid. Yield 42%; IR νmax (thin film)/cm-1 1609, 1370, 1259, 1176, 878. 1H NMR (600
MHz, CDCl3) δ 13.55 (s, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 6.37
(d, J = 2.6 Hz, 1H), 6.35 (d, J = 2.6 Hz, 1H), 5.01 (s, 2H), 2.62 (s, 3H), 2.55 (s, 3H),
2.36 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.0, 167.1, 163.5, 141.9, 138.1, 132.9,
129.4 (2×C), 127.7 (2×C), 115.2, 112.5, 100.0, 69.9, 33.0, 25.2, 21.2. HRMS (ESI) m/z
calcd for C17H19O3 [M + H]+ 271.1334, found 271.1335.
4.2.2.3.
1-(4-((4-fluorobenzyl)oxy)-2-hydroxy-6-methylphenyl)ethan-1-one
(9d).
Reagent: p-fluorobenzyl chloride. Followed the above procedure gave 9d as a white
solid. Yield 45%; IR νmax (thin film)/cm-1 2361, 2336, 1598, 1313. 1H NMR (600 MHz,
CDCl3) δ 13.54 (s, 1H), 7.38 (dd, J = 8.4, 5.3 Hz, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.36 (d,
J = 2.7 Hz, 1H), 6.35 (d, J = 2.7 Hz, 1H), 5.02 (s, 2H), 2.63 (s, 3H), 2.56 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 204.1, 167.1, 163.2, 162.7 (d, J = 246.8 Hz), 142.0, 131.8
(d, J = 3.2 Hz), 129.5 (d, J = 8.5 Hz, 2×C), 115.7, 115.49 (d, J = 26.8 Hz, 2×C), 112.4,
100.0, 69.3, 33.1, 25.2. HRMS (ESI) m/z calcd for C16H16O3F [M + H]+ 275.1083,
found 275.1091.
4.2.2.4. 1-(4-((4-chlorobenzyl)oxy)-2-hydroxy-6-methylphenyl)ethan-1-one (9e).
Reagent: p-chlorobenzyl chloride. Followed the above procedure gave 9e as a white
solid. Yield 51%; IR νmax (thin film)/cm-1 1611, 1370, 1258, 1176, 846. 1H NMR (600
MHz, CDCl3) δ 13.53 (s, 1H), 7.33 (m, 4H), 6.35 (s, 2H), 5.03 (s, 2H), 2.63 (s, 3H),
2.56 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.1, 167.1, 163.1, 142.0, 134.5, 134.1,
128.9 (2×C), 128.8 (2×C), 115.5, 112.4, 100.0, 69.1, 33.1, 25.2. HRMS (ESI) m/z calcd
for C16H16O3Cl [M + H]+ 291.0788, found 291.0798.
4.2.2.5.
1-(4-((4-bromobenzyl)oxy)-2-hydroxy-6-methylphenyl)ethan-1-one
(9f).
Reagent: p-bromobenzyl bromide. Followed the above procedure gave 9f as a white
15

solid. Yield 53%; IR νmax (thin film)/cm-1 1611, 1371, 1259, 1175, 875. 1H NMR (600
MHz, CDCl3) δ 13.52 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 6.35
(s, 2H), 5.01 (s, 2H), 2.63 (s, 3H), 2.57 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.1,
167.0, 163.1, 142.0, 135.0, 131.8 (2×C), 129.1 (2×C), 122.2, 115.5, 112.3, 100.0, 69.2,
33.1, 25.2. HRMS (ESI) m/z calcd for C16H16O3Br [M + H]+ 335.0283, found 335.0281.
4.2.2.6. 1-(4-((2,4-difluorobenzyl)oxy)-2-hydroxy-6-methylphenyl)ethan-1-one (9g).
Reagent: 2,4-difluorobenzyl bromide. Followed the above procedure gave 9g as a white
solid. Yield 47%; IR νmax (thin film)/cm-1 1615, 1505, 1266, 1171, 968, 836. 1H NMR
(600 MHz, CDCl3) δ 13.52 (s, 1H), 7.43 (dt, J = 8.4, 6.3 Hz, 1H), 6.91 (brt, J = 8.4 Hz,
1H), 6.86 (brt, J = 8.7 Hz, 1H), 6.39 (d, J = 2.6 Hz, 1H), 6.35 (d, J = 2.6 Hz, 1H), 5.07
(s, 2H), 2.63 (s, 3H), 2.57 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 204.1, 167.0, 163.0,
163.0 (dd, J = 250.0, 12.1 Hz), 160.7 (dd, J = 250.0, 12.1 Hz), 142.1, 130.9 (dd, J =
9.9, 5.5 Hz), 119.2 (dd, J = 14.5, 3.4 Hz), 115.5, 112.2, 111.6 (dd, J = 21.4, 3.9 Hz),
104.06 (t, J = 25.3 Hz), 99.9, 63.2, 33.1, 25.2. HRMS (ESI) m/z calcd for C16H15O3F2
[M + H]+ 293.0989, found 293.0998.
4.2.3. General procedure for the synthesis of compounds 10a-10g
The acetophenone 9a-9g, the acid 3 (1.0 eq.) and p-dimethylaminopyridine (0.2 eq.)
were dissolved in dichloromethane. Afterwards, N,N'-dicyclohexyl-carbimide (2.0 eq.)
were added portionwise. The reaction mixture was stirred for 20 h at room temperature,
filtered and the organic phase was washed with saturated sodium carbonate solution
and brine. After drying the solution over anhydrous Na2SO4, the solvent was removed
under reduced pressure and the residue was purified by silica gel column
chromatography EtOAc/Petroleum ether (1/5) as eluents.
4.2.3.1. 2-acetyl-5-methoxy-3-methylphenyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate
(10a). Followed the above procedure gave 10a as a colorless oil. Yield 85%; IR νmax
(thin film)/cm-1 2929, 1764, 1694, 1615, 1317, 1147, 1084, 1044. 1H NMR (600 MHz,
CDCl3) δ 6.55 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 3.95 (m, 4H), 3.72 (s, 3H),
13
2.82 (s, 2H), 2.38 (s, 3H), 2.23 (s, 3H), 1.49 (s, 3H); C NMR (150 MHz, CDCl3) δ
16

202.6, 167.5, 160.4, 148.4, 137.5, 127.4, 114.2, 107.6, 105.7, 65.0 (2×C), 55.5, 44.2,
32.1, 24.8, 20.0. HRMS (ESI) m/z calcd for C16H21O6 [M + H]+ 309.1338, found
309.1337.
4.2.3.2.2-acetyl-5-(benzyloxy)-3-methylphenyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate (
10b). Followed the above procedure gave 10b as a colorless oil. Yield 87%; IR νmax
(thin film)/cm-1 1764, 1694, 1611, 1317, 1146, 1083, 1044. 1H NMR (600 MHz, CDCl3)
δ 7.43 – 7.37 (m, 4H), 7.34 (m, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H),
13
5.04 (s, 2H), 4.01 (s, 4H), 2.88 (s, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.55 (s, 3H); C
NMR (150 MHz, CDCl3) δ 202.6, 167.5, 159.5, 148.3, 137.6, 136.2, 128.7 (2×C),
128.2, 127.6 (3×C), 114.9, 107.6, 106.6, 70.2, 64.9 (2×C), 44.2, 32.1, 24.8, 20.0. HRMS
(ESI) m/z calcd for C22H25O6 [M + H]+ 385.1651, found 385.1670.
4.2.3.3.2-acetyl-3-methyl-5-((4-methylbenzyl)oxy)-phenyl 2-(2-methyl-1,3-dioxolan-2-yl)
-
acetate (10c). Followed the above procedure gave 10c as a colorless oil. Yield 82%; IR
1
νmax (thin film)/cm-1 2927, 1764, 1694, 1611, 1352, 1145, 1082, 1044. H NMR (600
MHz, CDCl3) δ 7.29 (d, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 6.69 (d, J = 2.3 Hz,
1H), 6.59 (d, J = 2.3 Hz, 1H), 4.99 (s, 2H), 4.01 (s, 4H), 2.88 (s, 2H), 2.45 (s, 3H), 2.36
(s, 3H), 2.29 (s, 3H), 1.55 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 202.6, 167.5, 159.6,
148.4, 138.1, 137.5, 133.2, 129.4 (2×C) , 127.7 (2×C), 127.6, 115.0, 107.6, 106.6, 70.2,
65.0 (2×C), 44.2, 32.1, 24.8, 21.2, 20.0. HRMS (ESI) m/z calcd for C23H27O6 [M + H]+
399.1808, found 399.1830.
4.2.3.4.2-acetyl-5-((4-fluorobenzyl)oxy)-3-methylphenyl 2-(2-methyl-1,3-dioxolan-2-yl)
-
acetate (10d). Followed the above procedure gave 10d as a colorless oil. Yield 85%;
IR νmax (thin film)/cm-1 2928, 1764, 1694, 1612, 1512, 1421, 1223, 1146, 1083, 834. 1H
NMR (600 MHz, CDCl3) δ 7.38 (m, 2H), 7.08 (m, 2H), 6.69 (d, J = 2.4 Hz, 1H), 6.59
(d, J = 2.4 Hz, 1H), 4.99 (s, 2H), 4.01 (s, 4H), 2.88 (s, 2H), 2.46 (s, 3H), 2.29 (s, 3H),
13
1.55 (s, 3H); C NMR (150 MHz, CDCl3) δ 202.6, 167.5, 162.7 (d, J = 246.8 Hz),
159.3, 148.3, 137.6, 132.0 (d, J = 3.1 Hz), 129.5 (d, J = 8.6 Hz, 2×C), 127.8, 115.61 (d,
17

J = 22.0 Hz, 2×C), 114.9, 107.6, 106.6, 69.6, 65.0 (2×C), 44.2, 32.1, 24.8, 20.0. HRMS
(ESI) m/z calcd for C22H24O6F [M + H]+ 403.1557, found 403.1587.
4.2.3.5.2-acetyl-5-((4-chlorobenzyl)oxy)-3-methylphenyl 2-(2-methyl-1,3-dioxolan-2-
yl)-acetate (10e). Followed the above procedure gave 10e as a colorless oil. Yield 86%;
IR νmax (thin film)/cm-1 2931, 1763, 1694, 1611, 1379, 1146, 1085, 1045. 1H NMR (600
MHz, CDCl3) δ 7.36 (m, 2H), 7.34 (m, 2H), 6.68 (d, J = 2.4 Hz, 1H), 6.59 (d, J = 2.4
Hz, 1H), 5.00 (s, 2H), 4.01 (s, 4H), 2.88 (s, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.55 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 202.6, 167.5, 159.3, 148.3, 137.6, 134.7, 134.0, 128.9
(2×C), 128.8 (2×C), 127.9, 114.9, 107.6, 106.6, 69.4, 65.0 (2×C), 44.2, 32.1, 24.8, 20.0.
HRMS (ESI) m/z calcd for C22H24O6Cl [M + H]+ 419.1261, found 419.1280.
4.2.3.6. 2-acetyl-5-((4-bromobenzyl)oxy)-3-methylphenyl 2-(2-methyl-1,3-dioxolan-2-yl)
-acetate (10f). Followed the above procedure gave 10f as a colorless oil. Yield 89%; IR
1
νmax (thin film)/cm-1 2932, 1762, 1694, 1611, 1316, 1146, 1075, 1045. H NMR (600
MHz, CDCl3) δ 7.51 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.68 (d, J = 2.4 Hz,
1H), 6.58 (d, J = 2.4 Hz, 1H), 4.99 (s, 2H), 4.01 (s, 4H), 2.88 (s, 2H), 2.45 (s, 3H), 2.29
(s, 3H), 1.55 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 202.6, 167.5, 159.2, 148.3, 137.6,
135.3, 131.8 (2×C), 129.1 (2×C), 127.9, 122.1, 114.9, 107.6, 106.6, 69.4, 65.0 (2×C),
44.2, 32.1, 24.8, 20.0. HRMS (ESI) m/z calcd for C22H24O6Br [M + H]+ 463.0756,
found 463.0762.
4.2.3.7.
2-acetyl-5-((2,4-difluorobenzyl)oxy)-3-methylphenyl
2-(2-methyl-1,3-
dioxolan-2-yl)-acetate (10g). Followed the above procedure gave 10g as a colorless oil.
Yield 83%; IR νmax (thin film)/cm-1 2929, 1764, 1695, 1611, 1144, 1095, 1045, 850. 1H
NMR (600 MHz, CDCl3) δ 7.44 (td, J = 8.4, 6.4 Hz, 1H), 6.91 (m, 1H), 6.85 (ddd, J =
9.9, 8.8, 2.5 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H), 5.05 (s, 2H),
4.02 (s, 4H), 2.89 (s, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 1.55 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 202.6, 167.6, 163.0 (dd, J = 250.0, 11.9 Hz), 160.7 (dd, J = 250.0, 11.9 Hz),
159.1, 148.3, 137.6, 130.9 (dd, J = 9.9, 5.5 Hz), 128.0, 119.4 (dd, J = 14.7, 3.8 Hz),
114.8, 111.6 (dd, J = 21.4, 3.8 Hz), 107.6, 106.6, 104.0 (t, J = 25.4 Hz), 64.9 (2×C),
18

63.4, 44.2, 32.1, 24.8, 20.0. HRMS (ESI) m/z calcd for C22H23O6F2 [M + H]+ 421.1463,
found 421.1465.
4.2.4. General procedure for the synthesis of compounds 11a-11g
The ester 10a-10g was dissolved in THF under N2 atmosphere. At 0 °C, the
suspension of sodium hydride (20 eq.) was injected through a syringe gradually. The
mixture was slowly heated to reflux and stirred for 3.5 h. Then, reaction mixture was
cooled to 0 oC and added EtOAc and neutralized with hydrochloric acid until neutral.
Then extracted with EtOAc. The combined organic extracts were washed with brine
and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by silica gel column chromatography EtOAc/Petroleum ether
(1/4) as eluents.
4.2.4.1.
2-hydroxy-7-methoxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-
yl)methyl)chroman-4-one (11a). Followed the above procedure gave 11a as a white
solid. Yield 92%; IR νmax (thin film)/cm-1 3402, 2929, 1606, 1451, 1153, 1042. 1H NMR
(600 MHz, CDCl3) δ 6.30 (d, J = 2.6 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.92 (brs, 1H),
3.98 (m, 4H), 3.75 (s, 3H), 2.75 (s, 2H), 2.55 (s, 3H), 2.34 (d, J = 14.8 Hz, 1H), 2.03
(d, J = 14.8 Hz, 1H), 1.54 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.0, 164.3, 161.3,
143.7, 113.4, 112.1, 109.7, 100.9, 99.9, 64.8, 64.3, 55.4, 50.2, 45.2, 26.1, 23.1. HRMS
(ESI) m/z calcd for C16H21O6 [M + H]+ 309.1338, found 309.1339.
4.2.4.2. 7-(benzyloxy)-2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-
chroman-4-one (11b). Followed the above procedure gave 11b as a light yellow solid.
Yield 90%; IR νmax (thin film)/cm-1 3416, 1675, 1605, 1451, 1155, 1038. 1H NMR (600
MHz, CDCl3) δ 7.39 (m, 4H), 7.34 (m, 1H), 6.46 (d, J = 2.5 Hz, 1H), 6.36 (d, J = 2.5
Hz, 1H), 6.00 (brs, 1H), 5.06 (m, 2H), 4.03 (m, 4H), 2.82 (s, 2H), 2.62 (s, 3H), 2.40 (d,
J = 14.7 Hz, 1H), 2.09 (d, J = 14.7 Hz, 1H), 1.58 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 191.0, 163.4, 161.3, 143.8, 136.1, 128.7 (2×C), 128.2, 127.5 (2×C), 113.5, 112.7,
109.7, 100.9, 100.9, 70.0, 64.8, 64.3, 50.2, 45.1, 26.1, 23.1. HRMS (ESI) m/z calcd for
C22H25O6 [M + H]+ 385.1651, found 385.1649.
19

4.2.4.3.
2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-7-((4-
methylbenzyl)-oxy)chroman-4-one (11c). Followed the above procedure gave 11c as a
light yellow solid. Yield 85%; IR νmax (thin film)/cm-1 2925, 1676, 1606, 1570, 1451,
1276, 1154, 1803. 1H NMR (600 MHz, CDCl3) δ 7.29 (d, J = 7.8 Hz, 2H), 7.20 (d, J =
7.8 Hz, 2H), 6.44 (dd, J = 2.5, 0.9 Hz, 1H), 6.36 (d, J = 2.5 Hz, 1H), 5.99 (s, 1H), 5.02
(d, J = 3.3 Hz, 2H), 4.04 (m, 4H), 2.82 (s, 2H), 2.61 (s, 3H), 2.40 (d, J = 14.7 Hz, 1H),
13
2.36 (s, 3H), 2.09 (d, J = 14.7 Hz, 1H), 1.58 (s, 3H); C NMR (150 MHz, CDCl3) δ
191.0, 163.5, 161.3, 143.7, 138.1, 133.1, 129.4 (2×C), 127.7 (2×C), 113.5, 112.7, 109.7,
100.9, 100.9, 70.0, 64.8, 64.3, 50.2, 45.1, 26.1, 23.1, 21.2. HRMS (ESI) m/z calcd for
C23H27O6 [M + H]+
399.1808, found 399.1817.
4.2.4.4. 7-((4-fluorobenzyl)oxy)-2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)-
methyl)chroman-4-one (11d). Followed the above procedure gave 11d as a light yellow
solid. Yield 87%; IR νmax (thin film)/cm-1 3326, 2928, 1606, 1570, 1225, 1153, 833. 1H
NMR (600 MHz, CDCl3) δ 7.38 (m, 2H), 7.08 (m, 2H), 6.44 (d, J = 2.5 Hz, 1H), 6.35
(d, J = 2.5 Hz, 1H), 6.01 (m, 1H), 5.03 (m, 2H), 4.04 (m, 4H), 2.82 (s, 2H), 2.62 (s,
3H), 2.40 (d, J = 14.7 Hz, 1H), 2.10 (d, J = 14.7 Hz, 1H), 1.59 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 191.0, 163.2, 162.6 (d, J = 246.8 Hz), 161.3, 143.9, 131.9 (d, J = 3.2
Hz), 129.4 (d, J = 8.0 Hz, 2×C), 115.6 (d, J = 22.0 Hz, 2×C), 113.7, 112.6, 109.7, 101.0,
100.9, 69.4, 64.8, 64.3, 50.3, 45.1, 26.1, 23.1. HRMS (ESI) m/z calcd for C22H24O6F
[M + H]+ 403.1557, found 403.1563.
4.2.4.5. 7-((4-chlorobenzyl)oxy)-2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)-
methyl)chroman-4-one (11e). Followed the above procedure gave 11e as a light yellow
solid. Yield 89%; IR νmax (thin film)/cm-1 3329, 2927, 1676, 1606, 1451, 1155, 1087,
1041, 845. 1H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.5 Hz,
2H), 6.44 (d, J = 2.7 Hz, 1H), 6.33 (d, J = 2.7 Hz, 1H), 6.00 (s, 1H), 5.04 (m, 2H), 4.04
(m, 4H), 2.82 (s, 2H), 2.62 (s, 3H), 2.40 (d, J = 14.7 Hz, 1H), 2.10 (d, J = 14.7 Hz, 1H),
1.58 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.0, 163.1, 161.3, 143.9, 134.6, 134.1,
20

128.9 (2×C), 128.8 (2×C), 113.7, 112.6, 109.7, 101.0, 100.9, 69.2, 64.8, 64.3, 50.3,
45.1, 26.1, 23.1. HRMS (ESI) m/z calcd for C22H24O6Cl [M + H]+ 419.1261, found
419.1260.
4.2.4.6. 7-((4-bromobenzyl)oxy)-2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)-
methyl)chroman-4-one (11f). Followed the above procedure gave 11f as a light yellow
solid. Yield 91%; IR νmax (thin film)/cm-1 3400, 2928, 1605, 1570, 1451, 1312, 1155,
1040, 887. 1H NMR (600 MHz, CDCl3) δ 7.52 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz,
2H), 6.43 (d, J = 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 6.00 (s, 1H), 5.03 (m, 2H), 4.04
(m, 4H), 2.82 (s, 2H), 2.62 (s, 3H), 2.40 (d, J = 14.7 Hz, 1H), 2.10 (d, J = 14.7 Hz, 1H),
1.58 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 191.0, 163.0, 161.2, 143.9, 135.2, 131.8
(2×C), 129.1 (2×C), 122.2, 113.7, 112.6, 109.7, 101.0, 100.9, 69.2, 64.8, 64.3, 50.2,
45.1, 26.0, 23.1. HRMS (ESI) m/z calcd for C22H24O6Br [M + H]+ 463.0756, found
463.0758.
4.2.4.7. 7-((2,4-difluorobenzyl)oxy)-2-hydroxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)-
methyl)chroman-4-one (11g). Followed the above procedure gave 11g as a light yellow
solid. Yield 86%; IR νmax (thin film)/cm-1 3411, 2928, 1676, 1606, 1572, 1275, 1153,
1040, 849. 1H NMR (600 MHz, CDCl3) δ 7.44 (td, J = 8.4, 6.3 Hz, 1H), 6.91 (m, 1H),
6.86 (ddd, J = 10.0, 8.8, 2.5 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 6.37 (d, J = 2.5 Hz, 1H),
6.01 (s, 1H), 5.08 (s, 2H), 4.06 (m, 4H), 2.82 (s, 2H), 2.62 (s, 3H), 2.41 (d, J = 14.8 Hz,
13
1H), 2.10 (d, J = 14.8 Hz, 1H), 1.60 (s, 3H); C NMR (150 MHz, CDCl3) δ 191.0,
163.0 (dd, J = 250.0, 11.9 Hz), 162.9, 161.3, 160.6 (dd, J = 250.0, 11.9 Hz), 143.9,
130.9 (dd, J = 9.7, 5.2 Hz), 119.3 (dd, J = 14.5, 4.0 Hz), 113.8, 112.5, 111.6 (dd, J =
21.4, 3.8 Hz), 109.7, 104.00 (t, J = 25.4 Hz), 101.0, 100.7, 64.8, 64.3, 63.2, 50.2, 45.2,
26.1, 23.1. HRMS (ESI) m/z calcd for C22H23O6F2 [M + H]+ 421.1463, found 421.1468.
4.2.5. General procedure for the synthesis of compounds 12a-12g
A solution of 11a-11g in methanol was treated with anhydrous potassium carbonate
(3.0 eq.) at room temperature and the mixture was stirred 24 h. Filtered and evaporated
the filtrate at reduced pressure, and the residue is taken up in DCM, washed with 10%
21

aqueous hydrochloric acid and brine and dried over anhydrous Na2SO4. The solvent
removed at reduced pressure and the residue was purified by silica gel column
chromatography EtOAc/Petroleum ether (1/3) as eluents.
4.2.5.1. 7-methoxy-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-chromen-4-
one (12a). Followed the above procedure gave 12a as a light yellow solid. Yield 75%;
1H NMR (600 MHz, CDCl3) δ 6.63 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.07
13
(s, 1H), 3.94-3.84 (m, 4H), 3.79 (s, 3H), 2.79 (s, 2H), 2.74 (s, 3H), 1.39 (s, 3H); C
NMR (150 MHz, CDCl3) δ 179.5, 162.4, 162.3, 159.8, 142.6, 116.3, 116.2, 114.0,
108.5, 98.4, 65.0 (2×C), 55.6, 43.4, 24.8, 23.0.
4.2.5.2. 7-(benzyloxy)-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-chromen-
4-one (12b). Followed the above procedure gave 12b as a light yellow solid. Yield 77%;
IR νmax (thin film)/cm-1 2975, 2833, 2721, 1651, 1606, 1394, 1154. 1H NMR (600 MHz,
CDCl3) δ 7.42 (m, 4H), 7.36 (m, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H),
6.17 (s, 1H), 5.12 (s, 2H), 4.04-3.79 (m, 4H), 2.87 (s, 2H), 2.81 (s, 3H), 1.46 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 179.5, 162.5, 161.5, 159.7, 142.7, 135.9, 128.7 (2×C),
128.3, 127.5 (2×C), 116.8, 116.4, 113.8, 108.4, 99.4, 70.2, 65.0 (2×C), 43.4, 24.8, 23.0.
HRMS (ESI) m/z calcd for C22H23O5 [M + H]+ 367.1545, found 367.1547.
4.2.5.3. 5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-7-((4-methylbenzyl)oxy)-4H-
chromen-4-one (12c). Followed the above procedure gave 12c as a light yellow solid.
Yield 72%; IR νmax (thin film)/cm-1 2930, 1651, 1607, 1383, 1276, 1160, 1044. 1H NMR
(600 MHz, CDCl3) δ 7.32 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 6.79 (d, J = 2.5
Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.25 (s, 1H), 5.07 (s, 2H), 3.95 (m, 4H), 2.88 (s, 2H),
13
2.80 (s, 3H), 2.37 (s, 3H), 1.46 (s, 3H); C NMR (150 MHz, CDCl3) δ 179.5, 162.8,
161.7, 159.8, 142.7, 138.3, 132.8, 129.4 (2×C), 127.7 (2×C), 117.0, 116.1, 113.6, 108.4,
99.4, 70.2, 65.0 (2×C), 43.5, 24.8, 23.1, 21.2. HRMS (ESI) m/z calcd for C23H25O5 [M
+ H]+ 381.1702, found 381.1719.
4.2.5.4. 7-((4-fluorobenzyl)oxy)-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-
chromen-4-one (12d). Followed the above procedure gave 12d as a light yellow solid.
22

Yield 74%; IR νmax (thin film)/cm-1 2928, 1651, 1607, 1351, 1276, 1224, 1154, 1045,
1
831. H NMR (600 MHz, CDCl3) δ 7.41 (m, 2H), 7.10 (m, 2H), 6.77 (d, J = 2.5 Hz,
1H), 6.75 (d, J = 2.5 Hz, 1H), 6.19 (s, 1H), 5.07 (s, 2H), 3.96 (m, 4H), 2.87 (s, 2H),
13
2.81 (s, 3H), 1.46 (s, 3H); C NMR (150 MHz, CDCl3) δ 179.5, 162.7 (d, J = 246.8
Hz), 162.5, 161.3, 159.7, 142.8, 131.6 (d, J = 3.3 Hz), 129.4 (d, J = 8.8 Hz, 2×C), 116.7,
116.4, 115.7 (d, J = 21.1 Hz, 2×C), 113.8, 108.4, 99.4, 69.6, 65.0 (2×C), 43.4, 24.8,
23.0. HRMS (ESI) m/z calcd for C22H22O5F [M + H]+ 385.1451, found 385.1476.
4.2.5.5. 7-((4-chlorobenzyl)oxy)-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-
chromen-4-one (12e). Followed the above procedure gave 12e as a light yellow solid.
Yield 76%; IR νmax (thin film)/cm-1 2929, 1651, 1607, 1383, 1277, 1159, 1091, 1045,
1
851. H NMR (600 MHz, CDCl3) δ 7.37 (m, 4H), 6.77 (s, 2H), 6.28 (s, 1H), 5.09 (s,
2H), 3.96 (m, 4H), 2.89 (s, 2H), 2.81 (s, 3H), 1.46 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 179.5, 163.0, 161.4, 159.8, 142.9, 134.3, 134.2, 128.9 (2×C), 128.8 (2×C), 116.9,
116.2, 113.5, 108.4, 99.4, 69.5, 65.0 (2×C), 43.5, 24.8, 23.1. HRMS (ESI) m/z calcd for
C22H22O5Cl [M + H]+ 401.1156, found 401.1163.
4.2.5.6. 7-((4-bromobenzyl)oxy)-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-
chromen-4-one (12f). Followed the above procedure gave 12f as a light yellow solid.
Yield 76%; IR νmax (thin film)/cm-1 2927, 1651, 1608, 1384, 1159, 1096, 1044. 1H NMR
(600 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.75 (s, 2H),
6.17 (s, 1H), 5.07 (s, 2H), 3.97 (m, 2H), 3.92 (m, 2H), 2.87 (s, 2H), 2.81 (s, 3H), 1.46
(s, 3H); 13C NMR (150 MHz, CDCl3) δ 179.4, 162.5, 161.2, 159.7, 142.8, 134.9, 131.9
(2×C), 129.1 (2×C), 122.3, 116.7, 116.5, 113.9, 108.4, 99.5, 69.4, 65.0 (2×C), 43.4,
24.8, 23.0. HRMS (ESI) m/z calcd for C22H22O5Br [M + H]+ 445.0651, found 445.0668.
4.2.5.7. 7-((2,4-difluorobenzyl)oxy)-5-methyl-2-((2-methyl-1,3-dioxolan-2-yl)methyl)-4H-
chromen-4-one (12g). Followed the above procedure gave 12g as a light yellow solid.
Yield 72%; IR νmax (thin film)/cm-1 2927, 1651, 1607, 1385, 1278, 1160, 1102, 851. 1H
NMR (600 MHz, CDCl3) δ 7.47 (td, J = 8.4, 6.2 Hz, 1H), 6.93 (m, 1H), 6.88 (m, 1H),
6.80 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H), 6.19 (s, 1H), 5.12 (s, 2H), 3.96 (m,
23

4H), 2.88 (s, 2H), 2.81 (s, 3H), 1.46 (s, 3H); 13C NMR (150 MHz, CDCl3) δ179.5, 163.1
(dd, J = 250.0, 11.9 Hz), 162.6, 161.1, 160.6 (dd, J = 250.0, 11.9 Hz), 159.7, 142.9,
130.9 (dd, J = 9.7, 5.2 Hz), 119.3 (dd, J = 14.5, 4.0 Hz), 116.6 (2×C), 113.9, 111.6 (dd,
J = 21.4, 3.8 Hz), 108.4, 104.1 (t, J = 25.4 Hz), 99.4, 65.0 (2×C), 63.5, 43.4, 24.8, 23.0.
HRMS (ESI) m/z calcd for C22H21O5F2 [M + H]+ 403.1357, found 403.1359.
4.2.6. General procedure for the synthesis of compounds 13a-13g
To a solution of 11a-11g in DCM is added neat trimethylsilyl iodide (1.5 eq.)
o
through a pipette at 0 C and the mixture was stirred for 20 min. The excess
trimethylsilyl iodide is destroyed by adding methanol (5.0 eq.). The volatile
components are removed at reduced pressure and the residue is taken up in DCM,
washed with aqueous sodium bisulfite, aqueous sodium bicarbonate and brine and dried
over anhydrous Na2SO4. The solvent removed at reduced pressure and the residue was
purified by silica gel column chromatography EtOAc/Petroleum ether (1/3) as eluents.
4.2.6.1. 7-methoxy-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one (13a). Followed the
1
above procedure gave 13a as a light yellow solid. Yield 82%; H NMR (600 MHz,
CDCl3) δ 6.62 (d, J = 2.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.03 (s, 1H), 3.79 (s, 3H),
13
3.55 (s, 2H), 2.73 (s, 3H), 2.22 (s, 3H); C NMR (150 MHz, CDCl3) δ 201.5, 179.3,
162.6, 159.7, 159.3, 142.8, 116.4, 116.2, 113.8, 98.5, 55.6, 48.6, 29.8, 23.0.
4.2.6.2. 7-(benzyloxy)-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one (13b). Followed
the above procedure gave 13b as a light yellow solid. Yield 80%; IR νmax (thin film)/cm-
1
1 2926, 1652, 1607, 1453, 1384, 1159. H NMR (600 MHz, CDCl3) δ 7.41 (m, 4H),
7.36 (m, 1H), 6.79 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 6.20 (s, 1H), 5.12 (s,
13
2H), 3.64 (s, 2H), 2.81 (s, 3H), 2.29 (s, 3H); C NMR (150 MHz, CDCl3) δ 201.3,
179.3, 161.8, 159.7, 159.7, 142.9, 135.7, 128.8 (2×C), 128.4, 127.5 (2×C), 117.2, 116.1,
113.6, 99.4, 70.3, 48.6, 29.8, 23.1. HRMS (ESI) m/z calcd for C20H19O4 [M + H]+
323.1283, found 323.1292.
4.2.6.3. 5-methyl-7-((4-methylbenzyl)oxy)-2-(2-oxopropyl)-4H-chromen-4-one (13c).
Followed the above procedure gave 13c as a light yellow solid. Yield 78%; IR νmax (thin
24

1
film)/cm-1 2925, 1653, 1608, 1383, 1158. H NMR (600 MHz, CDCl3) δ 7.31 (d, J =
7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.80 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H),
13
6.31 (s, 1H), 5.08 (s, 2H), 3.66 (s, 2H), 2.80 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H); C
NMR (150 MHz, CDCl3) δ 201.2, 179.3, 162.1, 160.2, 159.9, 142.9, 138.3, 132.6, 129.5
(2×C), 127.7 (2×C), 117.4, 115.7, 113.2, 99.4, 70.3, 48.6, 29.8, 23.1, 21.2. HRMS (ESI)
m/z calcd for C21H21O4 [M + H]+ 337.1440, found 337.1452.
4.2.6.4. 7-((4-fluorobenzyl)oxy)-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one (13d).
Followed the above procedure gave 13d as a light yellow solid. Yield 81%; IR νmax
(thin film)/cm-1 2924, 1652, 1607, 1512, 1384, 1225, 1156, 831. 1H NMR (600 MHz,
CDCl3) δ 7.41 (m, 2H), 7.10 (m, 2H), 6.77 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H),
6.13 (s, 1H), 5.07 (s, 2H), 3.63 (s, 2H), 2.81 (s, 3H), 2.29 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ201.4, 179.3, 162.7 (d, J = 246.8 Hz), 161.5, 159.6, 159.5, 142.9, 131.6 (d, J
= 3.3 Hz), 129.4 (d, J = 8.6 Hz, 2×C), 117.0, 116.3, 115.7 (d, J = 21.1 Hz, 2×C), 113.8,
99.4, 69.6, 48.6, 29.8, 23.0. HRMS (ESI) m/z calcd for C20H18O4F [M + H]+ 341.1189,
found 341.1198.
4.2.6.5. 7-((4-chlorobenzyl)oxy)-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one (13e).
Followed the above procedure gave 13e as a light yellow solid. Yield 79%; IR νmax (thin
film)/cm-1 2925, 1652, 1607, 1384, 1278, 1159. 1H NMR (600 MHz, CDCl3) δ 7.37 (m,
4H), 6.78 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.25 (s, 1H), 5.09 (s, 2H), 3.65
(s, 2H), 2.81 (s, 3H), 2.29 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 201.2, 179.3, 161.6,
159.9, 159.8, 143.0, 134.3, 134.2, 129.0 (2×C), 128.8 (2×C), 117.2, 116.1, 113.5, 99.5,
69.5, 48.6, 29.8, 23.1. HRMS (ESI) m/z calcd for C20H18O4Cl [M + H]+ 357.0894, found
357.0909.
4.2.6.6. 7-((4-bromobenzyl)oxy)-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one (13f).
Followed the above procedure gave 13f as a light yellow solid. Yield 81%; IR νmax (thin
film)/cm-1 2925, 1653, 1607, 1383, 1282, 1159. 1H NMR (600 MHz, CDCl3) δ 7.54 (d,
J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.71 (d, J = 2.5 Hz,
1H), 6.23 (brs, 1H), 5.07 (s, 2H), 3.65 (s, 2H), 2.81 (s, 3H), 2.29 (s, 3H); 13C NMR (150
25

MHz, CDCl3) δ 201.2, 179.3, 161.6, 159.9, 159.7, 143.0, 134.8, 131.9 (2×C), 129.1
(2×C), 122.4, 117.1, 116.2, 113.5, 99.5, 69.5, 48.6, 29.8, 23.1. HRMS (ESI) m/z calcd
for C20H18O4Br [M + H]+ 401.0388, found 401.0390.
4.2.6.7.
7-((2,4-difluorobenzyl)oxy)-5-methyl-2-(2-oxopropyl)-4H-chromen-4-one
(13g). Followed the above procedure gave 13g as a light yellow solid. Yield 77%; IR
1
νmax (thin film)/cm-1 2927, 1651, 1607, 1278, 1160, 1102, 851. H NMR (600 MHz,
CDCl3) δ 7.46 (td, J = 8.4, 6.3 Hz, 1H), 6.93 (m, 1H), 6.88 (ddd, J = 10.0, 8.7, 2.6 Hz,
1H), 6.77 (d, J = 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.18 (s, 1H), 5.12 (s, 2H), 3.65
13
(d, J = 2.9 Hz, 2H), 2.81 (s, 3H), 2.30 (s, 3H); C NMR (150 MHz, CDCl3) δ 201.3,
179.2, 163.0 (dd, J = 250.1, 12.0 Hz), 161.6, 161.3, 160.6 (dd, J = 250.1, 12.0 Hz),
159.7, 143.0, 130.8 (dd, J = 9.7, 5.4 Hz), 119.3 (dd, J = 14.6, 3.7 Hz), 116.9, 116.4,
113.7, 111.6 (dd, J = 21.4, 3.8 Hz), 104.0 (t, J = 25.4 Hz), 99.3, 63.5, 48.6, 29.8, 23.0.
HRMS (ESI) m/z calcd for C20H17O4F2 [M + H]+ 359.1095, found 359.1110.
4.2.7. Synthesis of compound 16
A solution of 11a (50 mg, 0.162 mmol) in DCM (3.0 mL) was treated with
imidazole (13 mg, 0.194 mmol) and tert-butyldimethylsilyl chloride (37 mg, 0.243
mmol) at room temperature and the mixture was stirred overnight. The reation mixture
was diluted with DCM, washed with sat. aq. ammonium chloride solution and brine,
and dried over anhydrous Na2SO4. Filtration, conentration, and silica gel column
chromatography (EtOAc/petroleum ether = 1:8) gave the 16 (24.0 mg, 35%); IR νmax
1
(thin film)/cm-1 2955, 2933, 1601, 1467, 1333, 1257, 1197, 1158, 1046, 838, 783. H
NMR (600 MHz, CDCl3) δ 15.51 (s, 1H), 6.20 (d, J = 2.4 Hz, 1H), 6.05 (d, J = 2.4 Hz,
1H), 5.65 (s, 1H), 3.84 – 3.75 (m, 4H), 3.60 (s, 3H), 2.49 (s, 2H), 2.12 (s, 3H), 1.29 (s,
13
3H), 0.76 (s, 9H), 0.00 (s, 6H); C NMR (150 MHz, CDCl3) δ 189.0, 188.1, 160.8,
154.1, 138.8, 122.6, 108.7, 108.4, 105.7, 103.3, 64.8 (2×C), 55.2, 48.0, 25.6 (3×C),
24.5, 20.3, 18.1, -4.4 (2×C). HRMS (ESI) m/z calcd for C22H35O6Si [M + H]+ 423.2203,
found 423.2199.
4.2.8. General procedure for the synthesis of compounds 17a-17g
26

A solution of 11a-11g in acetone was cooled to 0 °C and the reaction flask was
covered with aluminium foil to protect the catalyst from light. PdCl2(CH3CN)2 (cat.)
was then added. The reaction is maintained at 0 °C and monitored by NMR for
completion, the dark orange reaction mixture was diluted with EtOAc and was washed
with ice cold brine. The organic phase was dried over anhydrous Na2SO4, the solvent
removed at reduced pressure and the residue was purified by silica gel column
chromatography EtOAc/Petroleum ether (1/4) as eluent.
4.2.8.1. 2-hydroxy-7-methoxy-5-methyl-2-(2-oxopropyl)chroman-4-one (17a).
1
Followed the above procedure gave 17a as a light yellow solid. Yield 92%; H NMR
(600 MHz, CDCl3) δ 6.38 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 6.03 (s, 1H),
3.80 (s, 3H), 3.26 (d, J = 16.7 Hz, 1H), 2.78 (s, 2H), 2.72 (d, J = 16.7 Hz, 1H), 2.61 (s,
13
3H), 2.33 (s, 3H); C NMR (150 MHz, CDCl3) δ 209.2, 190.0, 164.4, 161.0, 143.8,
113.3, 112.6, 100.7, 99.9, 55.4, 49.3, 48.8, 32.3, 23.1.
4.2.8.2. 7-(benzyloxy)-2-hydroxy-5-methyl-2-(2-oxopropyl)chroman-4-one (17b).
1
Followed the above procedure gave 17b as a light yellow solid. Yield 90%; H NMR
(600 MHz, CDCl3) δ 7.38 – 7.30 (m, 4H), 7.27 (m, 1H), 6.40 (d, J = 2.6 Hz, 1H), 6.28
(d, J = 2.6 Hz, 1H), 5.97 (s, 1H), 5.04 – 4.92 (m, 2H), 3.19 (d, J = 16.8 Hz, 1H), 2.71
(d, J = 1.5 Hz, 2H), 2.64 (d, J = 16.7 Hz, 1H), 2.54 (s, 3H), 2.25 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 209.2, 190.0, 163.5, 161.0, 143.8, 136.1, 128.7 (2×C), 128.3, 127.5
(2×C), 113.5, 113.3, 100.8, 100.7, 70.0, 49.3, 48.8, 32.3, 23.1.
4.2.8.3.2-hydroxy-5-methyl-7-((4-methylbenzyl)oxy)-2-(2-oxopropyl)chroman-4-one(
17c). Followed the above procedure gave 17c as a light yellow solid. Yield 91%; IR
1
νmax (thin film)/cm-1 3394, 2924, 1675, 1606, 1451, 1277, 1155. H NMR (600 MHz,
CDCl3) δ 7.29 (d, J = 7.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 6.46 (d, J = 2.5 Hz, 1H),
6.34 (d, J = 2.5 Hz, 1H), 6.03 (s, 1H), 5.00 (m, 2H), 3.25 (d, J = 16.7 Hz, 1H), 2.78 (s,
2H), 2.71 (d, J = 16.7 Hz, 1H), 2.61 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H); 13C NMR (150
MHz, CDCl3) δ 209.2, 190.0, 163.6, 160.9, 143.8, 138.1, 133.0, 129.4 (2×C), 127.6
27

(2×C), 113.4, 113.3, 100.7, 100.7, 70.0, 49.3, 48.8, 32.2, 23.1, 21.2. HRMS (ESI) m/z
calcd for C21H23O5 [M + H]+ 355.1545, found 355.1563.
4.2.8.4.7-((4-fluorobenzyl)oxy)-2-hydroxy-5-methyl-2-(2-oxopropyl)chroman-4-one(
17d). Followed the above procedure gave 17d as a light yellow solid. Yield 93%; IR
1
νmax (thin film)/cm-1 3395, 1675, 1605, 1512, 1225, 1154, 832. H NMR (600 MHz,
CDCl3) δ 7.37 (m, 2H), 7.08 (m, 2H), 6.45 (d, J = 2.5 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H),
6.06 (brs, 1H), 5.00 (m, 2H), 3.26 (d, J = 16.7 Hz, 1H), 2.79 (s, 2H), 2.72 (d, J = 16.7
Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 209.2, 190.0, 163.3,
162.7 (d, J = 246.8 Hz), 161.0, 143.9, 131.8 (d, J = 3.2 Hz), 129.4 (d, J = 8.1 Hz, 2×C),
115.6 (d, J = 21.7 Hz, 2×C), 113.6, 113.2, 100.8, 100.8, 69.4, 49.3, 48.8, 32.2, 23.1.
HRMS (ESI) m/z calcd for C20H20O5F [M + H]+ 359.1295, found 395.1312.
4.2.8.5.7-((4-chlorobenzyl)oxy)-2-hydroxy-5-methyl-2-(2-oxopropyl)chroman-4-one (
17e). Followed the above procedure gave 17e as a light yellow solid. Yield 92%; IR
νmax (thin film)/cm-1 3396, 1675, 1605, 1276, 1156. 1H NMR (600 MHz, CDCl3) δ 7.36
(d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.45 (d, J = 2.5 Hz, 1H), 6.31 (d, J = 2.5
Hz, 1H), 6.05 (s, 1H), 5.01 (m, 2H), 3.25 (d, J = 16.8 Hz, 1H), 2.78 (s, 2H), 2.72 (d, J
= 16.8 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 209.2, 190.0,
163.2, 160.9, 143.9, 134.6, 134.1, 128.9 (2×C), 128.8 (2×C), 113.6, 113.2, 100.8 (2×C),
69.2, 49.3, 48.8, 32.2, 23.1. HRMS (ESI) m/z calcd for C20H20O5Cl [M + H]+ 375.0999,
found 375.1012.
4.2.8.6.7-((4-bromobenzyl)oxy)-2-hydroxy-5-methyl-2-(2-oxopropyl)chroman-4-one(
17f). Followed the above procedure gave 17f as a light yellow solid. Yield 92%; IR νmax
1
(thin film)/cm-1 3398, 1675, 1605, 1276, 1155, 1052. H NMR (600 MHz, CDCl3) δ
7.52 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 6.45 (d, J = 2.5 Hz, 1H), 6.31 (d, J =
2.5 Hz, 1H), 6.05 (s, 1H), 5.00 (m, 2H), 3.25 (d, J = 16.8 Hz, 1H), 2.78 (s, 2H), 2.72
(d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.32 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 209.2,
190.0 163.1, 160.9, 143.9, 135.1, 131.8 (2×C), 129.0 (2×C), 122.2, 113.6, 113.2, 100.8
28

(2×C), 69.2, 49.3, 48.8, 32.2, 23.1. HRMS (ESI) m/z calcd for C20H20O5Br [M + H]+
419.0494, found 419.0495.
4.2.8.7.7-((2,4-difluorobenzyl)oxy)-2-hydroxy-5-methyl-2-(2-oxopropyl)chroman-4-one
(
17g). Followed the above procedure gave 17g as a light yellow solid. Yield 91%; IR
νmax (thin film)/cm-1 3396, 1677, 1606, 1275, 1155. 1H NMR (600 MHz, CDCl3) δ 7.44
(td, J = 8.4, 6.3 Hz, 1H), 6.91 (tdd, J = 8.2, 2.5, 1.1 Hz, 1H), 6.86 (ddd, J = 10.0, 8.8,
2.5 Hz, 1H), 6.46 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.05 (s, 1H), 5.06 (s,
2H), 3.26 (d, J = 16.8 Hz, 1H), 2.79 (s, 2H), 2.72 (d, J = 16.8 Hz, 1H), 2.62 (s, 3H),
13
2.33 (s, 3H); C NMR (150 MHz, CDCl3) δ 209.2, 190.0, 163.0 (dd, J = 250.1, 12.0
Hz), 163.0, 160.9, 160.6 (dd, J = 250.1, 12.0 Hz), 144.0, 130.8 (dd, J = 9.7, 5.4 Hz),
119.3 (dd, J = 14.6, 3.7 Hz), 113.7, 113.02, 111.6 (dd, J = 21.4, 3.8 Hz), 104.0 (t, J =
25.4 Hz), 100.8, 100.7, 63.3, 49.3, 48.8, 32.3, 23.1. HRMS (ESI) m/z calcd for
C20H19O5F2 [M + H]+ 377.1201, found 377.1212.
4.2.9. Synthesis of compound 18
To a stirred solution of 11b (200 mg, 0.52mmol) in MeOH (20 mL) was added in
one portion 5% Pd on C (200 mg). The reaction vessel was successively evacuated and
purged with H2 (1 atm) several times and stirred vigorously for overnight. The mixture
was then filtered through Celite, and the filter pad was washed with copious amounts
of MeOH and the filtrate was concentrated in vacuo to afford phenol (176 mg, quant.)
as a light yellow solid; B: Followed the procedure of 11a-11g, 19 as the material, yield
65%; 1H NMR (600 MHz,CDCl3) δ 7.44 (brs, 1H), 6.35 (d, J = 2.4 Hz, 1H), 6.31 (d, J
= 2.4 Hz, 1H), 6.06 (s, 1H), 4.06 (m, 4H), 2.84 (m, 2H), 2.60 (s, 3H), 2.41 (d, J = 14.8
Hz, 1H), 2.11 (d, J = 14.8 Hz, 1H), 1.60 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 192.0,
162.0, 161.6, 144.4, 113.3, 113.0, 109.7, 102.2, 100.8, 64.8, 64.3, 50.0, 45.2, 26.0, 23.1.
HRMS (ESI) m/z calcd for C15H18O6Na [M + Na]+ 317.1001, found 317.0996.
4.2.10. Synthesis of compound 19
Followed the procedure of 10a-10g, 5 as the material, the acid 3 (2.2 eq.) and p-
dimethylaminopyridine (0.2 eq.), N,N'-dicyclohexylcarbimide (4.0 eq.), gave 19 as a
29