Total synthesis of bysspectin A

Article abstract of DOI:10.1016/j.tet.2019.04.047

Bysspectin A (1), an unusual polyketide-derived octaketide dimer, has highly selective inhibitory activities against human carboxylesterase 2 (hCE2) with an IC₅₀ value of 2.01 μM. Herein, we report the first synthesis of this natural product. The synthesis relies upon a key Cu-catalysed domino Sonogashira-cyclization process.

Full text of DOI:10.1016/j.tet.2019.04.047

Accepted Manuscript
Total synthesis of bysspectin A
Feilong Yang, Xiaoyu Liu, Xiang Shi, Yong Wang, Guoru Hu, Sheng Lin, Xiaozhen
Jiao, Ping Xie
PII:
S0040-4020(19)30459-4
https://doi.org/10.1016/j.tet.2019.04.047
TET 30292
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2019
Revised Date: 28 March 2019
Accepted Date: 20 April 2019
Please cite this article as: Yang F, Liu X, Shi X, Wang Y, Hu G, Lin S, Jiao X, Xie P, Total synthesis of
bysspectin A, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.04.047.
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Total Synthesis of Bysspectin A
Leave this area blank for abstract info.
Feilong Yanga, Xiaoyu Liua, Xiang Shia, Yong Wanga,
Guoru Hub, Sheng Linc, Xiaozhen Jiaoa,* and Ping Xiea,*
No. 2, Nanwei Road, Xicheng District, Beijing

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total Synthesis of Bysspectin A
Feilong Yanga, Xiaoyu Liua, Xiang Shia, Yong Wanga, Guoru Hub, Sheng Linc, Xiaozhen Jiaoa, and Ping
Xiea,*
aState Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability
Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
bCollege of Life Science and Technology Bioinformatics, Huazhong University of Science and Technology, Wuhan 430074, China
cState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College, Beijing 100050, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Bysspectin A (1), an unusual polyketide-derived octaketide dimer, has highly selective
inhibitory activities against human carboxylesterase 2 (hCE2) with an IC50 value of 2.01 µM.
Herein, we report the first synthesis of this natural product. The synthesis relies upon a key Cu-
catalysed domino Sonogashira-cyclization process.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
bysspectin A
total synthesis
hCE2 inhibitor
domino sonogashira-cyclization
1. Introduction
inhibitor can be used to relieve the toxicity and side effect of
these anticancer drugs12. Thus, bysspectin A, which shows strong
inhibition against hCE2, may be a promising molecule as an
auxiliary agent in the field of cancer therapy.
Natural products containing 2-arylbenzofuran skeleton have
previously been reported with a diverse range of biological
activities and as such have the potential to be used in the
treatment of a variety of diseases. Of particular note is their
antioxidative, anti-inflammatory, cytotoxic behaviours1-3 as well
In light of the unique structure and promising biological
activities, we have developed a facile strategy to prepare
bysspectin A via a domino Sonogashira-cyclisation process,
which will enable further pharmaceutical development. Herein,
we report the first total synthesis of bysspectin A.
as their inhibition of protein tyrosine phosphatase 1B4-6
,
pancreatic lipase7, BsFtsZ8, tyrosinase9, as well as displaying
pronounced AChE and BChE inhibitory activities10.
Recently, bysspectin A (1) (Figure 1) was isolated from the
endophytic fungus Byssochlamys spectabilis found in traditional
Chinese
medical
plants,
Edgeworthia
chrysantha
(Thymelaeaceae family)11. It has a novel carbon skeleton
possessing two long and bulky hydrophobic aliphatic ketone
chains coupled with a 2-phenylbenzo[b]furan core. Our previous
biological activity assays showed that bysspectin A was a highly
selective inhibitor against human carboxylesterase 2 (hCE2) with
an IC50 value of 2.01 µM, two folds more active than the positive
control loperamide (LPA)11. hCE2 is an important
carboxylesterases in human intestine and functions to mediate
the drug metabolism. For example, hCE2 plays an important role
Figure 1. The structure of bysspectin A
.
in the metabolic activation of some anticancer drugs and hCE2
———
Corresponding author. E-mail: jiaoxz@imm.ac.cn, xp@imm.ac.cn;
Fax: +86 10 63017757; Tel: +86 10 63165242.

2
Tetrahedron
2. Results and discussion
from building blocks B and 2 through a domino Sonogashira-
ACCEPTED MANUSCRIPT
cyclization process13-19 and subsequent deprotection of the
phenolic hydroxyl group. Compound B and 2, can be readily
accessed from iodide C.
Our retrosynthetic analysis of bysspectin A (1) is outlined in
scheme 1. It was anticipated that compound 1 could be obtained
Scheme 1. Retrosynthetic analysis of bysspectin A.
Based on the retrosynthetic analysis, the synthesis commenced
with preparation of compound 2 and B from known 3 which was
obtained from (3-methoxyphenyl)methanol via a 2 step protocol20
(Scheme 2). Grignard reaction of 2-iodo-3-methoxybenzaldehyde
with octylmagnesium bromide followed by Dess-Martin
oxidation afforded compound 5. Subsequent deprotection of
compound 5 with BBr3 produced phenol 2. Unfortunately,
Sonogashira cross-coupling reaction of compound
5 with
trimethylsilylacetylene afforded compound 6 in a low yield.
Scheme 2. Synthesis of compound 2 and 6.
We inferred that the steric hindrance originating from the
flexible alkyl chain gave rise to the observed low yield of the
Sonogashira reaction. To access the required compound 6
efficiently, we modified our synthetic strategy by adjusting the
sequence to introduce the required trimethylsilylacetylene and
octyl group (Scheme 3). Using a method similar to one
previously reported21, we produced known compound 7 from 3.
Subsequent Grignard reaction followed by oxidation produced
the desired compound 6 in 63% yield over three steps.
Scheme 3. Optimized route of compound 6.
TMS
O
TBAF.3H2O
O
H3CO
H3CO
7
7
O
O
THF:MeOH (3:1), rt
[Cu(phen)(PPh3)2]NO3
Cs2CO3
9 (99%)
OCH3
6
OH
+
O
O
Toluene, 110oC
I
O
O
O
HO
7
10 (80%)
Bysspectin A
2
Scheme 4. The synthesis of compound 10
After removal of the trimethylsilyl group, a Pd-catalyzed
domino Sonogashira-cyclization reaction was initially attempted
to construct the desired 2-substituted benzo[b]furan framework
(Table 1). Treatment of compound 2 with 9 in the presence of 5
mol% Pd(PPh3)2Cl2 and 10 mol% CuI resulted in only a small
amount of the desired product 10 but instead a relatively large
amount of the homodimer 10a (Table 1, entry 1)13. In an effort to
improve the yield of compound 10, various reaction conditions
were screened employing differing sources of palladium (Table

[Cu(phen)(PPh3)2]NO314, FeCl315 or ZnEt216 (Table 1, entry 9-12).
1, entry 2-8). Unfortunately, this approach proAveCd fCruEitlPesTs,EwDith MANUSCRIPT
the
As anticipated, no homocoupled product was found in the
reactions employing these catalysts and the Cu-mediated reaction
gave the best result (Table 1, entry 9). However, the subsequent
deprotection of the methyl group afforded a complex mixture
(Scheme 4).
yield of compound 10 only partially improving. Considering the
fact22 that Pd catalytic domino Sonogashira-cyclization often
produced the homocoupled product 10a in large amounts, we
investigated the use of Pd-free conditions using catalysts such as
Table 1. The optimization of the transformation of compound 2 and 9 to benzofuran 10.a
Entry
Catalysts
Base
Solvent
Time
(h)
4
Temperature
Yield(%) of
10
Yield(%) of 10a
1
2
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)2Cl2, 10 mol% CuI
5 mol% Pd(PPh3)4, 10 mol% CuI
5 mol% Pd(OAc)2, 10 mol% CuI
10 mol% [Cu(phen)(PPh3)2]NO3
10 mol% [Cu(phen)(PPh3)2]NO3
5 mol% Et2Zn, 10 mol% DMEDA
5 mol% FeCl3, 10 mol% DMEDA
5 mol% FeCl3, 10 mol% o-Phenanthroline
Et3N
Et3N
DMF
DMF
80 oC
60 oC
80 oC
80 oC
80 oC
80 oC
80 oC
80 oC
110 oC
110 oC
125 oC
145 oC
145 oC
14.1
72.7
86.9
4
4
9.9
c
b
3
Cs2CO3
DMF
13.4
40.6
10.2
12.8
—
4
DIPEA
Et3N
DMF
4
47.8
67.5
79.5
5
Dioxane
Toluene
DMF
4
6
Et3N
4
b
b
7
Et3N
4
—
—
b
8
Et3N
DMF
4
—
77.4
c
b
9
Cs2CO3
Toluene
Toluene
CH3CN
Xylene
Xylene
4
79.8
—
c
b
10
11
12
13
K3PO4
4
54.7
—
c
b
b
K3PO4
12
36
36
—
—
d
d
b
b
Cs2CO3
Cs2CO3
—
—
b
44.0
—
aThe ratio of reactant 9 and 2 was 1.2:1 in Pd-mediated reactions, 1:1 in Cu-mediated and Zn-mediated reactions, and 1.5:1 in Fe-mediated reactions. All the
reactions were carried out under anhydrous and air free conditions.
bThe target compound was not detected.
c2 equiv. base was employed.
d4 equiv. Cs2CO3 was employed
Scheme 5. Synthesis of bysspectin A (1) using SEM protecting group.

4
Tetrahedron
ACCEPTED MANUSCRIPT
The failure of the deprotection of O-methyl group implied
5.3. 1-(2-iodo-3-methoxyphenyl)nonan-1-ol (4)
that a more easily removable protecting group was necessary for
the successful synthesis of bysspectin A. Therefore, a new
synthetic
To a solution of 3 (6.702 g, 25.575 mmol ) in anhydrous ether
(150 mL) was added octylmagnesium bromide (2 M, 15.345 mL,
30.690 mmol ) dropwise at 0 C under Ar. The mixture was
strategy
was
devised
(Scheme
5).
2-
o
(Trimethylsilyl)ethoxymethyl (SEM) protected 13 was obtained
via Sonogashira coupling reaction and subsequent protection of
phenol group23. Following a similar synthetic route as shown for
9, the required terminal alkyne 16 was produced in a good yield.
The aforementioned described domino Sonogashira-cyclization
reaction was then performed between 2 and 16, employing
[Cu(phen)(PPh3)2]NO3 as the catalyst, afforded 17 in 83% yield,
which is consistent with the previous results obtained in this
study. Finally, deprotection of benzofuran 17 using
tetrabutylammonium fluoride trihydrate afforded bysspectin A in
65% yield. The spectroscopic data of our synthesized bysspectin
A (1) were in excellent agreement with the data reported in the
literature.11
o
stirred for 0.5 h at 0 C before the complete consumption of 3
shown by TLC. Then the reaction was quenched with saturated
aqueous NH4Cl (110 mL). The solution was subsequently
extracted with ether (3 × 100 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography on a silica gel column (EtOAc/petroleum
ether=1/20) to afford 4 (7.314 g, 76%) as a colorless oil. TLC: Rf
(4) = 0.49 (petroleum ether/ethyl acetate = 5:1). IR (film)
νmax/cm−1 3437, 3345, 2919, 2853, 1566, 1466, 1423, 1266, 1062,
1
780; H NMR (CDCl3, 400 MHz): δ 7.30 (t, J = 8 Hz, 1H), 7.13
(d, J = 7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.02-5.00 (m, 1H),
3.89 (s, 3H), 2.08 (s, 1H), 1.78-1.73 (m, 1H), 1.64-1.27 (m, 13H),
0.88 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 157.5,
148.8, 129.3, 119.2, 109.7, 90.2, 77.6, 56.5, 37.7, 31.9, 29.5,
29.4, 29.2, 25.9, 22.6, 14.1; HRMS(ESIMS): calcd. for
C16H25O2NaI [M+Na]+: 399.0791, Found: 399.0794.
3. Conclusion
In summary, the first efficient synthesis of natural product
bysspectin A has been completed in thirteen steps with an overall
yield of 7.7% from commercially available (3-methoxyphenyl)
methanol. The strategy was based on a domino Sonogashira-
cyclization process to construct the benzofuran ring. The strategy
developed here can also be used for the synthesis of various
analogues of bysspectin A and the related work is in progress.
5.4. 1-(2-iodo-3-methoxyphenyl)nonan-1-one (5)
To a solution of 4 (7.261 g, 19.297 mmol) in dichloromethane
(150 mL) was added Dess-Martin periodinane (9.821 g, 23.156
mmol) at room temperature. The mixture was stirred for 1.5 h
before the complete consumption of 4 shown by TLC. Then the
reaction was quenched with saturated aqueous Na2SO3 (70 mL).
The solution was subsequently extracted with dichloromethane (3
× 100 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography on a silica gel
column (EtOAc/petroleum=1/20) to afford 5 (7.078 g, 98%) as a
yellow oil. TLC: Rf (5) = 0.47 (petroleum ether/ethyl acetate =
8:1). IR (film) νmax/cm−1 2926, 2854, 1703, 1563, 1463, 1419,
4. Experimental section
5.1. General description
All the solvents and reagents were purchased from
commercial suppliers. Flash column chromatography was
performed on Biotage Isolera one. IR spectra were recorded
on a Thermo Nicolet 5700 FT-IR microscope Centaurs
spectrophotometer. 1H NMR and 13C NMR were recorded
on Mercury 400, Bruker AV600 spectrometer. Coupling
constants are given in Hz and chemical shifts are expressed
1
1296, 1267, 1019, 780; H NMR (400 MHz, CDCl3): δ 7.33 (t, J
= 8.0 Hz, 1H), 6.83 (t, J = 7.6 Hz, 2H), 3.9 (s, 3H), 2.85 (t, J =
7.6 Hz, 2H), 1.71 (m, 2H), 1.37-1.27 (m, 10H), 0.87 (t, J = 6.8
Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 206.2, 158.1, 148.4,
129.5, 119.0, 111.5, 82.9, 56.6, 42.6, 31.7, 29.3, 29.1, 29.0, 23.8,
22.6, 14.0; HRMS(ESIMS): calcd. for C16H24O2I [M+H]+:
375.0816, Found: 375.0808.
as
δ values in ppm. The following multiplicity abbreviations
are used: (s) singlet, (d) doublet, (t) triplet, (q) quartet, (m)
multiplet. ESI-HRMS data were measured on Thermo
Exactive Orbitrap plus spectrometer.
5.2. 1-(3-hydroxy-2-iodophenyl)nonan-1-one (
2)
5.5. 1-(3-methoxy-2-((trimethylsilyl)ethynyl)phenyl)nonan-1-one
(6)
To a solution of (0.277 g, 0.740 mmol) in anhydrous
5
dichloromethane (20 mL), BBr3 (1M in dichloromethane,
o
1.258 mL) was added dropwise at -78 C under Ar. The
Method A: Trimethylsilylacetylene (20.183 mL, 142.815
mmol) was added to a suspension of 5 (10.690 g, 28.563 mmol),
Pd(PPh3)2Cl2 (0.401 g, 0.571 mmol), CuI (0,218 g, 1.413 mmol),
Et3N (14.81 mL, 106.540 mmol), and DMSO (70 mL) in a
mixture was slowly warmed to room temperature and stirred
for 4.5 h before the complete consumption of
5 shown by
TLC. Then the mixture was poured into ice-water. and
extracted with ether. The combined organic layers were
washed with saturated NaHCO3 and brine, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
o
Schlenk flask. This suspension was heated to 60 C and stirred
under Ar for 6 h. The mixture was poured into water (500 mL)
and extracted with dichloromethane (3 x 250 mL). The organic
extracts were dried (Na2SO4), filtered, concentrated in vacuo and
purified by flash chromatography on a silica gel column
(EtOAc/petroleum=1/40) to afford 6 (5.528 g, 42%) as a
colorless oil. TLC: Rf (6) = 0.71 (petroleum ether/ethyl acetate =
8:1).
column (EtOAc/petroleum=1/5) to afford
2 (0.197 g, 74%)
as a brown oil. TLC: Rf (2) = 0.23 (petroleum ether/ethyl
acetate = 4:1). IR (film) νmax/cm−1 3417, 2926, 2856, 1695,
1
1565, 1457, 1426, 1294, 1251, 1011,972, 859, 837, 785; H
NMR (400 MHz, CDCl3):
δ
7.27 (t,
J
= 7.6 Hz, 1H), 7.09
= 7.6 Hz, = 1.6
= 7.6 Hz, 2H), 1.71 (m, 2H),
= 6.8 Hz, 3H); 13C NMR
Method B:
6
as a colorless oil was prepared from
8
(dd, = 8.0 Hz, = 1.6 Hz 1H), 6.97 (dd,
J
J
J
J
following the procedure described for
5
in 98% yield. TLC:
Hz, 1H), 5.91 (s, 1H), 2.87 (t,
1.37-1.27 (m, 10H), 0.88 (t,
J
J
Rf (6) = 0.69 (petroleum ether/ethyl acetate = 8:1). IR (film)
νmax/cm−1 3018, 2961, 2927, 2853, 2153, 1696, 1586, 1571,
(CDCl3, 100 MHz):
δ 204.5, 155.5, 145.0, 129.8, 120.1,
1
1466, 1454, 1434, 1295, 1269, 996, 847, 761; H NMR
116.8, 83.8, 41.9, 31.8, 29.3, 29.2, 29.1, 24.1, 22.6, 14.1;
HRMS(ESIMS): calcd. for C15H22O2I [M+H]+: 361.0659,
Found: 361.0660.
(CDCl3, 400 MHz):
Hz, 1H), 6.94 (d,
7.6 Hz, 2H), 1.67 (m, 2H), 1.30-1.26 (m, 10H), 0.87 (t,
δ
7.30 (t,
J = 8 Hz, 1H), 7.03 (d, J = 7.6
J
= 8.4 Hz, 1H), 3.90 (s, 3H), 3.06 (t,
J
J
=
=

6.8 Hz, 3H), 0.26 (s, 9H); 13C NMR (CDCl3, 100 MHz):
205.2, 160.8, 145.3, 129.6, 119.2, 112.5, 109.6, 105.1, 98.9,
56.2, 42.7, 31.8, 29.4, 29.3, 29.1, 24.4, 22.6, 14.1, -0.2;
HRMS(ESIMS): calcd. for C21H33O2Si [M+H]+: 345.2244,
Found: 345.2243.
δ
ether/ethyl acetate = 8:1). IR (film) νmax/cm−1 2920, 2851, 1700,
ACCEPTED MANUSCRIPT
1679, 1582, 1468, 1426, 1271, 744; 1H NMR (400 MHz, CDCl3):
δ 7.95 (s,1H), 7.84 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.42 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 8 Hz, 1H), 7.09 (d, J = 8.4
Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H), 3.07 (t, J = 7.2
Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.80 (m, 2H), 1.60-1.57 (m,
2H), 1.43-1.13 (m, 20H), 0.88-0.82 (m, 6H) ;13C NMR (CDCl3,
100 MHz): δ 206.6, 200.9, 157.0, 154.9, 152.6, 143.0, 130.3,
130.0, 128.5, 124.7, 123.6, 119.2, 116.2, 115.5, 112.5, 109.6,
56.0, 42.6 , 39.4, 31.8, 31.7, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0,
24.5, 24.3, 22.6, 22.5, 14.1, 14.0; HRMS(ESIMS): calcd. for
C33H45O4 [M+H]+: 505.3312, Found: 505.3298.
5.6. 3-methoxy-2-((trimethylsilyl)ethynyl)benzaldehyde (7)
7 as a colorless oil was prepared from 3 following the method
B described for 6 in 90% yield. TLC: Rf (7) = 0.61 (petroleum
1
ether/ethyl acetate = 8:1). H NMR (CDCl3, 400 MHz): δ 10.55
(s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.08 (d,
J = 8.4 Hz, 1H), 3.91 (s, 3H), 0.28 (s, 9H); 13C NMR (CDCl3,
100 MHz): δ 192.0, 160.9, 137.5, 129.5, 118.7, 116.1, 115.6,
107.2, 95.9, 56.2, -0.2; HRMS(ESIMS): calcd. for C13H17O2Si
[M+H]+: 233.0992, Found: 233.0984.
5.10.
1,1'-(buta-1,3-diyne-1,4-diylbis(3-((2-
methoxy)-2,1-phenylene))bis(nonan-1-
(trimethylsilyl)ethoxy)
one) (10a)
5.7. 1-(3-methoxy-2-((trimethylsilyl)ethynyl)phenyl)nonan-1
-ol (8)
TLC: Rf (10a) = 0.48 (petroleum ether/ethyl acetate = 8:1). m.
p. 39-44 oC IR (film) νmax/cm−1 3082, 2924, 2854, 1773, 1687,
1586, 1567, 1468, 1437, 1294, 1274, 1003, 788, 739; H NMR
1
8
as a colorless oil was prepared from 7 following the
(400 MHz, CDCl3): δ 7.35 (t, J = 8.0 Hz, 2H), 7.15 (d, J = 7.6
Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.91 (s, 6H), 3.04 (t, J = 7.6
Hz, 4H), 1.73-1.68 (m, 4H), 1.37-1.23 (m, 24H), 0.84-0.81 (m,
6H); 13C NMR (CDCl3, 150 MHz): δ 203.6, 162.3, 145.0, 130.1,
119.9, 112.8, 108.9, 83.3, 78.0, 56.2, 42.2, 31.8, 29.4, 29.3, 29.1,
24.5, 22.6, 14.0; HRMS(ESIMS): calcd. for C36H47O4 [M+H]+:
543.3469, Found: 543.3478.
procedure described for
4 in 71% yield. TLC: Rf (8) = 0.45
(petroleum ether/ethyl acetate = 9:1). IR (film) νmax/cm−1
3376, 2957, 2926, 2855, 2152, 1596, 1574, 1470, 1438,
1271, 1250, 1082, 1059, 865, 844, 759; H NMR (CDCl3,
1
400 MHz):
1H), 6.75 (d,
3H), 2.23(d,
(m, 12H), 0.87 (t,
(CDCl3, 100 MHz):
δ
7.27 (t,
= 8.4 Hz, 1H), 5.12-5.08 (m, 1H), 3.87 (s,
= 4.4 Hz, 1H), 1.80-1.74 (m, 2H), 1.51-1.26
= 6.8 Hz, 3H), 0.28 (s, 9H); 13C NMR
160.4, 149.7, 129.6, 117.5, 109.5,
J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz,
J
J
J
5.11. 3-hydroxy-2-((trimethylsilyl)ethynyl)benzaldehyde (12)
δ
109.0, 104.5, 98.9, 72.6, 55.9, 38.1, 31.8, 29.6, 29.5, 29.2,
26.1, 22.6, 14.1, 0; HRMS(ESIMS): calcd. for C21H35O2Si
[M+H]+: 347.2401, Found: 347.2399.
12 as a light yellow solid was prepared from 11 following the
procedure described for 7 in 92% yield. TLC: Rf (12) = 0.71
o
(petroleum ether/ethyl acetate = 5:1). m. p. 68-72 C IR (film)
νmax/cm−1 3226, 2963, 2851, 2150, 1670, 1581, 1463, 1296, 1249,
5.8. 1-(2-ethynyl-3-methoxyphenyl)nonan-1-one (9)
1
1235, 846, 787; H NMR (CDCl3, 400 MHz): δ 10.39 (s, 1H),
7.49 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.36 (m, 1H), 7.21 (dd, J =
8.4 Hz, J = 1.2 Hz, 1H), 6.12 (s, 1H), 0.32 (s, 9H); 13C NMR
(CDCl3, 100 MHz): δ 190.9, 157.7, 136.4, 130.0, 120.0, 119.7,
112.3, 109.8, 94.7, -0.2; HRMS(ESIMS): calcd. for C12H15O2Si
[M+H]+: 219.0836, Found: 219.0830.
To a solution of
6 (1.821 g, 5.285 mmol) in THF:MeOH
(3:1) (60 mL), tetrabutylammonium fluoride trihydrate
(3.668 g, 11.627 mmol) was added. The suspension was
stirred for 1.5 h at room temperature until complete
conversion is detected by TLC. Then the suspension was
concentrated in vacuo. The residue was purified by flash
5.12.
3-((2-(trimethylsilyl)ethoxy)methoxy)-2-
chromatography
(EtOAc/petroleum=1/40) to afford
on
a
silica
gel
column
((trimethylsilyl) ethynyl)benzaldehyde (13
)
9
(1.425 g, 99%) as a
brown oil. TLC: Rf (
9
) = 0.65 (petroleum ether/ethyl acetate
To a solution of 12 (2.231 g, 10.218 mmol) in anhydrous
dichloromethane (100 mL) was added
= 8:1). IR (film) νmax/cm−1 3269, 2927, 2855, 2105, 1694,
1572, 1467, 1454, 1436, 1296, 1271, 1009, 741;1H NMR
diisopropylethylamine (7.60 mL, 45.981 mmol) and then 2-
(Trimethylsilyl)ethoxymethyl chloride (5.426 mL, 30.655
mol) dropwise at room temperature under Ar. The mixture
was stirred for 2 h before the complete consumption of 12
shown by TLC. Then the reaction was quenched with
saturated aqueous NaHCO3 (70 mL). The solution was
subsequently extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash chromatography on a silica gel column
(EtOAc/petroleum=1/50) to afford 13 (3.489 g, 75.8%) as a
brown oil. TLC: Rf (13) = 0.76 (petroleum ether/ethyl
acetate = 19:1). IR (film) νmax/cm−1 3378, 2957, 2901, 2856,
(400 MHz, CDCl3):
8.0 Hz, 1H), 6.96 (d,
1H), 2.97 (t, = 7.6 Hz, 2H), 1.66 (m, 2H), 1.33-1.23
(m,10H), 0.84 (t,
= 6.8 Hz, 3H); 13C NMR (CDCl3, 100
MHz): 204.2, 161.2, 145.0, 129.7, 119.2, 112.5, 108.4,
δ
7.32 (t,
J = 7.6 Hz, 1H), 7.05 (d, J =
J
= 8.4 Hz, 1H), 3.88 (s, 3H), 3.52 (s,
J
J
δ
86.5, 77.7, 56.1, 42.2, 31.7, 29.3, 29.1, 29.0, 24.2, 22.5,
14.0; HRMS(ESIMS): calcd. for C18H25O2 [M+H]+:
273.1849, Found: 273.1843.
5.9. 1-(3-methoxy-2-(4-nonanoylbenzofuran-2-yl)phenyl) nonan-
1-one (10)
A long needle was inserted into a solution of 2 (50 mg, 0.139
mmol) in anhydrous toluene (2 mL), bubbling the solution by
blowing argon. During this process, [Cu(phen)(PPh3)2]NO3 (12
mg, 0.014 mmol), Cs2CO3 (91 mg, 0.278 mmol) and a solution of
9 (37.9 mg, 0.139 mmol) in anhydrous toluene (1 mL) were
added into the mixture in turn. Then the suspension was heated to
110oC and stirred for 5 h until complete conversion was detected
by TLC. The suspension was cooled, filtered and concentrated in
vacuo. The residue was purified by flash chromatography on a
silica gel column (EtOAc/petroleum=1/30) to afford 10 (68.2 mg,
80.1%) as a yellow oil. TLC: Rf (10) = 0.67 (petroleum
2156, 1700, 1590, 1468, 1384, 1250, 1152, 1102, 1021, 861,
1
792, 762; H NMR (400 MHz, CDCl3):
δ 10.55 (s, 1H),
7.56 (t,
3.82 (m, 2H), 0.96 (m, 2H), 0.29 (s, 9H), -0.01(s, 9H); 13C
NMR (CDCl3, 100 MHz): 192.0, 158.9, 137.5, 129.3,
J = 4.4 Hz, 1H), 7.36-7.35 (m, 2H), 5.33 (s, 2H),
δ
120.2, 120.0, 117.3, 106.9, 96.0, 93.4, 66.7, 18.0, -0.1, -1.4;
HRMS(ESIMS): calcd. for C18H19O3Si2 [M+H]+: 349.1650,
Found: 349.1652.

6
Tetrahedron
5.13.
1-(3-((2-(trimethylsilyl)ethoxy)methoxy)-2-
J
= 7.8 Hz, 1H), 7.08 (d,
J
= 6.6 Hz, 1H), 5.35 (s, 2H), 3.75
= 8.4 Hz, 2H), 3.07 (t, = 7.2 Hz, 2H), 2.43 (t, = 7.2
Hz, 2H), 1.80 (m, 2H), 1.59-1.57 (m, 2H), 1.44-1.41 (m,
2H), 1.36-1.22 (m, 14H), 1.14-1.12 (m, 4H), 0.93 (t, = 8.4
Hz, 2H), 0.88 (t, = 6.6 Hz, 3H), 0.84 (t, = 7.2 Hz, 3H), -
0.05 (s, 9H); 13C NMR (CDCl3, 150 MHz):
206.4, 200.8,
ACCEPTED MANUSCRIPT
((trimethylsilyl)ethynyl)phenyl)nonan-1-ol (14
)
(t,
J
J
J
14 as a colorless oil was prepared from 13 following the
J
procedure described for
4 in 75% yield. TLC: Rf (14) = 0.38
J
J
(petroleum ether/ethyl acetate = 9:1). IR (film) νmax/cm−1
δ
3397, 3067, 2959, 2858, 2154, 1939, 1596, 1574, 1466,
155.1, 155.0, 152.6, 143.0, 130.2, 130.0, 128.4, 124.7,
123.6, 120.3, 117.2, 116.6, 115.5, 109.5, 93.3, 66.7, 42.5,
39.4, 31.9, 31.8, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 24.5,
24.3, 22.7, 22.6, 18.0, 14.1, 14.0, -1.5; HRMS(ESIMS):
calcd. for C38H56O5NaSi [M+Na]+: 643.3789, Found:
643.3772.
1250, 865, 756; 1H NMR (400 MHz, CDCl3):
δ
7.24 (t,
J =
8.0 Hz, 1H), 7.11 (d,
1H), 5.27 (s, 2H), 5.09-5.06 (m, 1H), 3.81 (m, 2H), 2.29-
2.25 (m, 1H), 1.80-1.70 (m, 2H), 1.53-1.49 (m, 1H), 1.33-
1.26 (m, 12H), 0.98-0.94 (m, 2H), 0.89-0.85 (t,
3H), 0.27 (s, 9H), 0.00 (s, 9H); 13C NMR (CDCl3, 100
MHz): 158.4, 149.4, 129.5, 118.6, 113.6, 111.0, 104.2,
J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz,
J = 6.8 Hz,
δ
5.17. 1-(3-hydroxy-2-(4-nonanoylbenzofuran-2-yl)phenyl)
99.0, 93.3, 72.7, 66.4, 38.0, 31.9, 29.6, 29.5, 29.3, 26.2,
22.6, 18.0, 14.1, 0.0, -1.4; HRMS(ESIMS): calcd. for
C26H47O3Si2 [M+H]+: 463.3058, Found: 463.3050.
nonan-1-one (1)
To a solution of 17 (130 mg, 0.209 mmol) in THF,
tetrabutylammonium fluoride trihydrate (660 mg, 2.094
mmol) was added. The mixture was heated to 45 C and
o
5.14.
1-(3-((2-(trimethylsilyl)ethoxy)methoxy)-2-
((trimethylsilyl)ethynyl)phenyl)nonan-1-one (15
)
stirred for 7 h until the complete conversion was detected by
TLC. The solution was concentrated in vacuo. Water was
added and then the solution was extracted with EtOAc . The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated. The residue
was purified by flash chromatography on a silica gel column
15 as a yellow oil was prepared from 14 following the
procedure described for
5 in 99% yield. TLC: Rf (15) = 0.65
(petroleum ether/ethyl acetate = 15:1). IR (film) νmax/cm−1
2956, 2927, 2856, 2157, 1692, 1588, 1569, 1453, 1251,
1
1102, 985, 864, 842, 760; H NMR (400 MHz, CDCl3):
δ
(EtOAc/petroleum=1/20) to afford
1 (66 mg, 60.8%) as a
7.29 (d,
1H), 7.10 (dd,
3.83-3.79 (m, 2H), 3.06 (t,
J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4 Hz, J = 1.2 Hz,
yellow oil. TLC: Rf (1) = 0.31 (petroleum ether/ethyl acetate
J
= 7.6 Hz,
J
= 1.2 Hz, 1H), 5.30 (s, 2H),
= 7.6 Hz, 2H), 1.68 (m, 2H),
= 7:1). IR (film) νmax/cm−1 3267, 2924, 2853, 1711, 1673,
J
1650, 1580, 1456, 1423, 1267; 1H NMR (600 MHz, CDCl3):
1.33-1.26 (m, 10H), 0.98-0.94 (m, 2H), 0.87 (t,
3H), 0.25 (s, 9H), 0.01 (s, 9H); 13C NMR (CDCl3, 100
MHz): 204.9, 158.8, 145.0, 129.4, 120.4, 117.0, 111.0,
J = 7.2 Hz,
δ
7.87 (d,
1H), 7.38 (t,
(d, = 7.8 Hz, 1H), 7.09 (d,
3.06 (t, = 7.8 Hz, 2H), 2.54 (t,
2H), 1.60-1.57 (m, 2H), 1.43-1.41 (m, 2H), 1.32-1.15 (m,
18H), 0.88 (t, = 6.6 Hz, 3H), 0.85 (t,
= 7.2 Hz, 3H); 13C
NMR (CDCl3, 150 MHz): 205.6, 200.9, 155.4, 154.1,
J
= 7.8 Hz, 1H), 7.85 (s, 1H), 7.66 (d,
= 8.4 Hz, 1H), 7.37 (t, = 7.8 Hz, 1H), 7.14
= 7.2 Hz, 1H), 6.47 (s, 1H),
= 7.8 Hz, 2H), 1.79 (m,
J = 8.4 Hz,
J
J
δ
J
J
104.8, 99.0, 93.3, 66.5, 42.6, 31.8, 29.4, 29.3, 29.1, 24.4,
22.6, 18.0, 14.0, -0.2, -1.4; HRMS(ESIMS): calcd. for
C26H45O3Si2 [M+H]+: 461.2902, Found: 461.2890.
J
J
J
J
δ
5.15.
1-(2-ethynyl-3-((2-(trimethylsilyl)ethoxy)methoxy)
152.4, 142.3, 130.8, 130.1, 127.9, 125.0, 124.2, 119.7,
118.5, 115.7, 113.9, 108.6, 42.1, 39.4, 31.9, 31.8, 29.5, 29.4,
29.3, 29.2, 29.1, 29.0, 24.5, 24.3, 22.7, 22.6, 14.1, 14.0;
HRMS(ESIMS): calcd. for C32H43O4 [M+H]+: 491.3156,
Found: 491.3151.
phenyl) nonan-1-one (16
)
To a solution of 15 (1.821 g, 3.952 mmol) in anhydrous
methanol (60 mL), K2CO3 (55 mg, 395 mmol) was added.
The suspension was stirred for 1.5 h at room temperature
until complete conversion was detected by TLC. Then the
suspension was concentrated in vacuo. The residue was
purified by flash chromatography on a silica gel column
(EtOAc/petroleum=1/50) to afford 16 (1.368 g, 89%) as a
yellow oil. TLC: Rf (16) = 0.38 (petroleum ether/ethyl
acetate = 10:1). IR (film) νmax/cm−1 3301, 3267, 2954, 2926,
2856, 2106, 1696, 1588, 1571, 1453, 1252, 1102, 987, 860,
Acknowledgments
This investigation was supported by CAMS Innovation Fund
for Medical Sciences (CIFMS, 2016-I2M-3-009) and the Drug
Innovation Major Project (2018ZX09711-001-005).
837, 745; 1H NMR (400 MHz, CDCl3):
7.26 (dd, = 8.4 Hz, = 1.2 Hz, 1H), 7.14 (dd,
= 1.2 Hz, 1H), 5.3 (s, 2H), 3.83-3.79 (m, 2H), 3.51 (s, 1H),
2.99 (t, = 7.6 Hz, 2H), 1.69 (m, 2H), 1.37-1.26 (m, 10H),
0.97-0.93 (m, 2H), 0.87 (t,
= 6.8 Hz, 3H), 0.00 (s, 9H); 13
NMR (CDCl3, 100 MHz): 204.1, 159.4, 145.0, 129.6,
δ
7.35-7.31 (m, 1H),
= 7.6 Hz,
References and notes.
J
J
J
J
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C
δ
120.4, 117.0, 109.7, 93.4, 86.3, 77.8, 66.6, 42.2, 31.8, 29.3,
29.2, 29.1, 24.2, 22.6, 18.0, 14.0, -1.5; HRMS(ESIMS):
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5.16. 1-(2-(2-nonanoyl-6-((2-(trimethylsilyl)ethoxy)methoxy
phenyl)benzofuran-4-yl)nonan-1-one (17
)
17 as a yellow oil was prepared from
the procedure described for 10 in 82.6% yield. TLC: Rf (17
2
and 16 following
)
= 0.59 (petroleum ether/ethyl acetate = 12:1). IR (film)
νmax/cm−1 3359, 3186, 3068, 2926, 2855, 1701, 1679, 1582,
1
1463, 1424, 1361, 1260, 1153, 1099, 982, 859, 837, 748; H
NMR (600 MHz, CDCl3):
δ 7.92 (s, 1H), 7.85 (d, J = 7.2
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J

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ACCEPTED MANUSCRIPT
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Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
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