3
Scheme 3. Synthetic Route for 1, 2, 3 and 4a
OH
OH
Br
O
O
OH
OH
O
73%
25%
j, k, d, f
HO
Br
HO
O
O
Br
f
OH
OH
2, Artoindonesianin B-1
38
Br
i
42
72%
Br
O
O
O
O
O
TBDMSO
j
k
18
36
O
O
O
99%
HO
O
O
94%
O
O
d
OH
76%
g
40%
O
41
O
O
O
39
37
40
O
O
e
a
d
c
b
B(OH)2
O
98%
TBDMSO
O
98%
84%
two steps
99%
TBDMSO
O
O
92%
TBDMSO
TBDMSO
TBDMSO
O
O
O
HO
35
32
33
34
17
31
f
57%
f
75%
OH
O
OH
OH
h
O
O
HO
HO
O
HO
OH
OH
4, Moracin M
1, Moracin C
3, Moracin D
aReagents and conditions: (a) TBDMSCl, imidazole, THF, rt, 4h; (b) NaBH4, MeOH, rt, 1h; (c) i. n-BuLi, THF, -78°C, 1h; ii. Triisopropyl
borate, -78°C to -30°C, 2h; iii. 2M HCl, pH=5.0; (d) i. 1-Bromo-3,5-dimethoxybenzene, Pd(OAc)2, Tricyclohexyl phosphine, K2CO3, DME,
H2O, 80°C, 2h; ii. TBDMSCl, imidazole, THF, rt, 2h; (e) i. n-BuLi, THF, 0°C to reflux, 30min; ii. 3,3-Dimethylallyl bromide, reflux, 2h; (f) n-
BuLi, Ph2PH, THF, 0°C to reflux, 36h; (g) n-BuLi, Ph2PH, THF, 0°C to reflux, 16h; (h) DDQ, benzene, dioxane, reflux 2h; (i) Isovaleryl
chloride, AlCl3, CH2Cl2, -5°C 2h; (j) LiAlH4, THF, 0°C, 2h; (k) p-TSA, PhCH3, reflux, 2h.
Scheme 4. Synthetic Route for Substituted 2-Arylbenzo[b]furansa
Acknowledgments
O
a
R
c
b
R
OH
R
R
Financial support of this research provided by the National
Natural Science Foundation of China (Grants 21222211,
21372001, 91313303), the Program for New Century Excellent
Talents in University (Grant NCET-12-0853), China
Postdoctoral Science Foundation grant (2014M551361), “Shu
Guang” project supported by Shanghai Municipal Education
Commission and Shanghai Education Development Foundation
(Grant 14SG28), and the Fundamental Research Funds for the
Central Universities is gratefully acknowledged.
O
OH
43, R = H,
44, R = 3-Fluoro,
45, R = 3-Methyl,
46, R = 4-Chloro
O
O
O
55-58
47-50
51-54
O
O
O
d
e
f
B(OH)2
R
R
R
O
O
O
O
59-62
67-70
63-66
OH
g
R
O
OH
71-74
aReagents and conditions: (a) i. BrCH2COOMe, K2CO3,DMF, r.t.
12h; ii. NaOH, MeOH, 2h; (b) i. SOCl2, reflux 4h; ii. AlCl3, CH2Cl2,
0°C to r.t. 30min; (c) NaBH4, MeOH, r.t. 1h; (d) i. n-BuLi, THF, -
78°C 1h; ii. Triisopropyl borate, -78°C to -30°C 2h; iii. 2M HCl,
Supplementary data
General information for chemical agents and analytical
measurements, detailed synthetic procedures and related
spectroscopic data for the compounds 1, 2, 4, and 71–74, HPLC
reports for the purity check of the compounds 1, 2, 4, and 71–74.
This material is available free of charge via the Internet at http://.
pH=5.0;
(e)
1-Bromo-3,5-dimethoxybenzene,
Pd(OAc)2,
Tricyclohexyl phosphine, K2CO3, DME, H2O, 80°C 2h; (f) Ph2PLi,
THF, reflux 12h.
Consequently, the synthetic route of moracin C (1) in Scheme
3 provided the best way for preparing enough amounts of 1 as
well as designed 2-arylbenzo[b]furan analogs of 1 to explore the
biological potential. And four 2-arylbenzo[b]furan-containing
natural product-like compounds (71–74, Scheme 4) were
prepared to determine the significance of substituent on phenyl
ring of benzo[b]furan for anti-inflammatory activities. The
detailed synthetic procedure and spectroscopic data for all the
compounds (1, 2, 4, and 71-74) are given in Supplementary
information. Further investigations for biological applications of
these natural products and anologs are underway in our group.
References and notes
1. Gutierrez, R. M. P.; Mitchell, S.; Solis, R. V. J. Ethnopharmacol. 2008,
117, 1–27.
2. Kabir, S. J. Immunol. Methods 1998, 212, 193–211.
3. Hakim, E. H.; Achmad, S. A.; Juliawaty, L. D.; Makmur, L.; Syah, Y.
M.; Aimi, N.; Kitajima, M.; Takayama, H.; Ghisalberti, E. L. J. Nat.
Med. 2006, 60, 161–184.
4. Sato, M.; Fujiwara, S.; Tsuchiya, H.; Fujii, T.; Iinuma, M.; Tosa, H.;
Ohkawa, Y. J. Ethnopharmacol. 1996, 54, 171–176.
5. Khan, M.; Omoloso, A.; Kihara, M. Fitoterapia 2003, 74, 501–505.
6. Likhitwitayawuid, K.; Sritularak, B.; Benchanak, K.; Lipipun, V.;
Mathew, J.; Schinazi, R. F. Nat. Prod. Res. 2005, 19, 177–182.
7. Chuanasa, T.; Phromjai, J.; Lipipun, V.; Likhitwitayawuid, K.; Suzuki,
M.; Pramyothin, P.; Hattori, M.; Shiraki, K. Antivir. Res. 2008, 80, 62–
70.
3. Conclusion
In summary, we successfully completed a concise route for the
synthesis of 2-arylbenzo[b]furans. Moracin C (1) and moracin M
(4), the natural products from Artocarpus, have been synthesized
in highest overall yield to date (1, 7 steps with an overall yield of
8. Jayasinghe, L.; Balasooriya, B.; Padmini, W. C.; Hara, N.; Fujimoto, Y.
Phytochemistry 2004, 65, 1287–1290.
9. Trindade, M. B.; Lopes, J. L.; Soares-Costa, A.; Monteiro-Moreira, A.
C.; Moreira, R. A.; Oliva, M. L. V.; Beltramini, L. M. BBA-Proteins
Proteom. 2006, 1764, 146–152.
41.9%; 4,
6 steps with an overall yield of 56.2%).
Artoindonesianin B-1 (2) has also been prepared in 8 steps with
an overall yield of 11.3%, which represents the first total
synthesis of the member of this family.
10. Fernando, M.; Wickramasinghe, S.; Thabrew, M.; Ariyananda, P.;
Karunanayake, E. J. Ethnopharmacol. 1991, 31, 277–282.
11. Takasugi, M.; Nagao, S.; Ueno, S.; Masamune, T.; Shirata, A.;
Takahashi, K. Chem. Lett. 1978, 7, 1239–1240.