Total synthesis of ribisin A

Article abstract of DOI:10.1016/j.tetlet.2013.12.052

The first total synthesis of natural product ribisin A has been achieved in 11 steps from commercially available methyl α-d-glucopyranoside with 21.6% overall yield. The highly oxygenated benzofuran skeleton of this natural product was constructed, taking advantages of the inherent chirality of d-glucose, through the key reactions of Ferrier carbocyclization, Johnson iodination, Suzuki cross-coupling, and Wacker oxidative cyclization.

Full text of DOI:10.1016/j.tetlet.2013.12.052

Tetrahedron Letters 55 (2014) 959–961
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ribisin A
⇑
Chaoli Zhang, Jun Liu, Yuguo Du
State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of natural product ribisin A has been achieved in 11 steps from commercially
Received 1 November 2013
Revised 6 December 2013
Accepted 17 December 2013
Available online 21 December 2013
available methyl
a
-
D
-glucopyranoside with 21.6% overall yield. The highly oxygenated benzofuran skel-
eton of this natural product was constructed, taking advantages of the inherent chirality of
through the key reactions of Ferrier carbocyclization, Johnson iodination, Suzuki cross-coupling, and
Wacker oxidative cyclization.
D-glucose,
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Ribisin A
Benzofuran
Total synthesis
Ferrier carbocyclization
Wacker oxidation
OH
OH
Phellinus ribis, a kind of fungi belonging to Phellinus gunus
(Hymenochaetaceae family), has been used for treating several dis-
eases and enhancing body immunity as a folk medicine in East
Asia.1 Recently, Fukuyama and coworker reported the isolation of
four new natural products as ribisin A–D (1–4, Fig. 1) from the
methanol extraction of the fruiting bodies of P. ribis.2 All of these
compounds have highly oxygenated benzofuran skeleton and
could stimulate neurite outgrowth in NGF-mediated PC12 cells.
The novel structure and the specific neural related biological activ-
ities attracted our interests in the total synthesis and SAR studies of
ribisin A–D. As part of our ongoing project for drug candidate prep-
aration using natural carbohydrates as chiral templates,3 we report
O
O
OH
OMe
OMe
OMe
O
O
1
2
Ribisin A,
Ribisin B,
HO
OH
OH
O
O
OMe
OMe
OMe
OMe
O
O
3
Ribisin C,
4
Ribisin D,
herein the first total synthesis of ribisn A from D-glucose derivative
applying Ferrier carbocyclization as a key transformation in the
Figure 1. Structure of ribisin A–D.
construction of highly oxygenated core skeleton.4
The retrosynthetic analysis of ribisin A (1) is depicted in
Scheme 1. The target compound 1 could be achieved from com-
pound 5 by establishing the benzofuran core structure through Su-
zuki cross-coupling and furan formation. The cyclohexenone 5 in
turn was envisioned to be synthesized from carbohydrate interme-
diate 6 utilizing Ferrier carbocyclization and the following Johnson
iodination. Compound 6 could be synthesized from commercially
procedure.5 Blocking two secondary hydroxyl groups of 8 with
tert-butyldimethylsilyl chloride (TBSCl) was conducted smoothly
using 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) as base giving
the desired product 9 in high yield. Reductive cleavage of the ben-
zylidene acetal 9 was achieved under Pd(OH)2/C catalyzed hydrog-
enolysis obtaining compound 10, which was subjected to the
regioselective iodination on primary hydroxyl group to generate
iodide derivative 11 in high yield.6 Treatment of iodide 11 with
MeI in the presence of excessive t-BuOK accomplished O-methyla-
tion on C4 and HI elimination between C5 and C6, forming the key
intermediate hexenopyranoside 6 in one pot.
available methyl
Synthesis of the key intermediate 6 from 7 is presented in
Scheme 2. The known methyl 4,6-O-benzylidene- -glucopyrano-
side (8) was readily obtained from the reaction of 7 with -dime-
a-D-glucopyranoside (7).
a-D
a,a
thoxytoluene and p-toluenesulfonic acid according to a literature
With the key intermediate 6 in hand, we then turned our atten-
tion to the Ferrier carbocyclization reaction (see Scheme 3). To get
a successful rearrangement, various metal catalysts, including
⇑
Corresponding author.
E-mail address: duyuguo@rcees.ac.cn (Y. Du).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.052

960
C. Zhang et al. / Tetrahedron Letters 55 (2014) 959–961
catalytic amounts of Hg(OAc)2, HgCl2, Hg(OCOCF3)2 and PdCl2,
O
O
MeO
HO
were screened.7 One of the major byproducts was isolated and pos-
tulated as an acyclic keto-aldehyde 19 based on NMR spectra anal-
yses (1H NMR, 2D COSY).8 This reminded us of using more amount
of catalyst, in the case of stereo-hindered substrate, to facilitate the
fast generation of vinyl alkoxide anion intermediate in the carbo-
cyclization. Indeed, the formation of compound 19 was almost
completely prevented when the reaction was proceeded in the
presence of 1.0 equiv of Hg(OAc)2 in 15 min, and the desired
b-hydroxyketone 12 was obtained as a mixture of stereoisomers
in 68.5% yield. Treatment of mixture 12 with methanesulfonyl
MeO
I
TBSO
O
HO
OTBS
1
5
Ribisin A,
OH
O
O
OMe
HO
chloride (MsCl) and TEA at room temperature afforded
a,b-unsat-
HO
MeO
OTBS
urated ketone 13, which was further converted into the
a
-iodoe-
HO
OMe
none 14 quantitatively applying Johnson’s iodination protocol.9
Suzuki cross-coupling10 of 14 with 2-hydroxyphenyl boronic acid
catalyzed by Pd2(PCy3)2 gave benzofuran precursor 15 in a yield
of 81%. Preparation of the core benzofuran structure was initially
designed through epoxidation of 15 (?16), following a cascade
epoxide-opening reaction (?17) and the elimination of hydroxy
OTBS
6
7
Scheme 1. Retrosynthetic analysis of ribisin A.
OH
O
O
O
c
a
b
Ph
O
Ph
O
O
O
HO
HO
TBSO
HO
HO
TBSO
HO
OMe
OMe
OMe
8
9
7
OH
O
OMe
I
O
O
HO
d
e
HO
TBSO
TBSO
TBSO
MeO
OTBS
TBSO
OMe
OMe
OTBS
10
11
6
Scheme 2. Reagents and conditions: (a) see Ref. 5, 80% (b) DBU, TBSCl, DCM, rt, 95%; (c) Pd(OH)2/C, MeOH, rt, 98%; (d) I2, PPh3, imidazole, THF, 60 °C, 98%; (e) MeI, t-BuOK,
THF, ꢀ30 °C to rt, 84%.
O
O
O
I
MeO
MeO
MeO
c
a
b
6
TBSO
TBSO
TBSO
OH
OTBS
12
OTBS
13
OTBS
14
(HO)2B
HO
d
O
MeO
O
MeO
f
g
Ribisin A, 1
TBSO
TBSO
TBSO
TBSO
O
HO
15
18
e
O
O
O
MeO
MeO
OH
O
MeO
O
TBSO
TBSO
TBSO
TBSO
TBSO
O
HO
OTBS
19
17
16
Scheme 3. Reagents and conditions: (a) Hg(OAc)2, acetone/H2O (v/v, 4:1), rt, 68.5%; (b) MsCl, TEA, DCM, rt, 95%; (c) I2, CCl4/pyridine (v/v, 1:1), rt, 99%; (d) Pd2(PCy3)2, 1 M
aqueous Na2CO3/toluene/MeOH, 65 °C, 81%; (e) mCPBA, DCM, rt; (f) PdCl2, CuCl, O2, dioxane, 50 °C, 69%; (g) TBAF, THF, rt, 98%.

C. Zhang et al. / Tetrahedron Letters 55 (2014) 959–961
961
group under acid conditions (?18).11 To our surprise, mCPBA or
H2O2 promoted oxidation of 15 generated mixtures of complex
and unidentified products. Palladium(II)-catalyzed Wacker reac-
tion, a widely applied industrial process for olefin transformation
and heterocycle construction through anti oxypalladation,12 was
thus investigated. As we expected, Wacker oxidative cyclization
of 15 with PdCl2/CuCl/O2 was carried out smoothly at 50 °C in
moisture-containing dioxane affording the desired product 18 in
a yield of 69%. Global deprotection of 18 with TBAF in THF fur-
nished the target compound ribisin A (1), whose spectroscopic data
were identical to those of the natural product.13
Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118–2121; (d)
Barton, D. H. R.; Camara, J.; Dalko, P.; Géro, S. D.; Quiclet-Sire, B.; Stütz, P. J. Org.
Chem. 1989, 54, 3764–3766.
8. (a) Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron Lett.
1999, 55, 3855–3870; (b) 1H NMR (400 MHz, CDCl3) data for 19: d 9.81 (s, 1H),
4.27 (d, J = 6.0 Hz, 1H), 3.95 (d, J = 6.0 Hz, 1H), 3.71 (s, 1H), 3.26 (s, 3H), 2.24 (s,
3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.00 (s,
3H) ppm.
9. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.; Wockulich, P. M.;
Uskokovic´, M. R. Tetrahedron Lett. 1992, 33, 917–918.
10. Pandey, G.; Balakrishnan, M.; Swaroop, P. S. Eur. J. Org. Chem. 2008, 5839–5847.
11. Aslam, S. N.; Stevenson, P. C.; Phythian, S.; Veitch, N. C.; Hall, D. R. Tetrahedron
2006, 62, 4214–4226.
12. (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94; (b) Reiter, M.;
Turner, H.; Mills-Webb, R.; Gouverneur, V. J. Org. Chem. 2005, 70, 8478–8485;
(c) Youn, S. W.; Eom, J. I. Org. Lett. 2005, 7, 3355–3358; (d) Liao, X.; Zhou, H.;
Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501–3504; (e) Hayashi, T.;
Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037.
In conclusion, we have successfully achieved the first total syn-
thesis of ribisin A from commercially available methyl
a-D-gluco-
pyranoside in 11 steps and in 21.6% overall yield. Our synthetic
procedure, employing sequential Ferrier carbocyclization, Johnson
iodination, Suzuki cross coupling, and Wacker oxidative cyclization
as key steps, offers a concise and efficient synthetic route toward
highly oxygenated benzofuran compounds.
13. Spectroscopic data for selected compounds: Compound 11: ½a D22
ꢁ
+193.4 (c 1,
CHCl3). 1H NMR (400 MHz, CDCl3) d = 4.68 (d, J = 3.2 Hz, 1H), 3.80 (t, J = 8.8 Hz,
1H), 3.59–3.55 (m, 2H), 3.52–3.47 (m, 1H), 3.43 (s, 3H), 3.29 (dd, J = 10.4,
7.6 Hz, 1H), 3.21 (t, J = 8.8 Hz, 1H), 0.91 (d, J = 1.6 Hz, 18 H), 0.12 (s, 6H), 0.09 (s,
6H) ppm. 13C NMR (100 MHz, CDCl3) d = 100.0, 75.1, 74.5, 73.6, 70.4, 55.3, 26.1,
26.0, 18.3, 18.1, 7.1, ꢀ3.4, ꢀ3.6, ꢀ4.3, ꢀ4.5 ppm. HRMS (ESI) calcd for
C
19H41IO5Si2Na [(M+Na)+] 555.1429, found 555.1438. Compound 6: a 2D2
½ ꢁ
+78.0 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3) d = 4.69–4.67 (m, 3H), 3.77 (t,
J = 8.8 Hz, 1H), 3.66 (dd, J = 8.8, 3.6 Hz, 1H), 3.48 (s, 1H), 3.40–3.37 (m, 4H),
0.92–0.91 (m, 18H), 0.12–0.09 (m, 12H) ppm. 13C NMR (100 MHz, CDCl3)
d = 153.9, 101.1, 95.9, 82.7, 74.1, 73.8, 59.9, 55.3, 26.1, 26.0, 18.3, 18.1, ꢀ3.6,
ꢀ3.7, ꢀ4.3, ꢀ4.6 ppm. HRMS (ESI) calcd for C20H42O5Si2Na [(M+Na)+] 441.2462,
Acknowledgments
This work was supported by the MOST of China (Projects
2012ZX09502001-001 and 2012CB822101) and NNSF of China
(Projects 21072217 and 21202193).
found 441.2475. Compound 13: ½a D22
ꢁ
+217.6 (c 1, CHCl3). 1H NMR (400 MHz,
CDCl3) d = 6.71 (dd, J = 10.4, 1.6 Hz, 1H), 5.98 (dd, J = 10.4, 3.6 Hz, 1H), 4.40 (dt,
J = 6.0, 2.0 Hz, 1H), 3.80 (dd, J = 10.4, 8.0 Hz, 1H), 3.60 (s, 1H), 3.50 (d,
J = 10.4 Hz, 1H), 0.93–0.91 (m, 18H), 0.16–0.08 (m, 12H) ppm. 13C NMR
(100 MHz, CDCl3) d = 198.2, 151.5, 127.2, 86.5, 78.3, 73.9, 60.7, 26.1, 26.0,
18.2, 18.1, ꢀ3.6, ꢀ3.9, ꢀ4.2, ꢀ4.7 ppm. HRMS (ESI) calcd for C19H38O4Si2Na
Supplementary data
[(M+Na)+] 409.2201, found 409.2200. Compound 14: ½a 2D2
ꢁ
+93.2 (c 1.5, CHCl3).
Supplementary data (experimental procedures, spectral charac-
terization, and copies of 1H and 13C NMR data) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.12.052.
1H NMR (400 MHz, CDCl3) d = 7.44 (d, J = 2.4 Hz, 1H), 4.37 (dd, J = 7.6, 2.4 Hz,
1H), 3.82 (dd, J = 10.4, 7.6 Hz, 1H), 3.59–3.56 (m, 4H), 0.93 (s, 9H), 0.90 (s, 9H),
0.16 (d, J = 4.4 Hz, 6H), 0.08 (d, J = 5.6 Hz, 6H) ppm. 13C NMR (100 MHz, CDCl3)
d = 192.2, 159.1, 101.4, 84.6, 77.7, 75.4, 60.4, 26.0, 18.1, 18.0, ꢀ3.7, ꢀ4.0, ꢀ4.3,
ꢀ4.7 ppm. HRMS (ESI) calcd for C19H37IO4Si2Na [(M+Na)+] 535.1167, found
535.1180. Compound 15: ½a D22
ꢁ
ꢀ118.2(c 1, CHCl3). 1H NMR (400 MHz, CDCl3)
References and notes
d = 7.67 (s, 1H), 7.31–7.26 (m, 2H), 7.03–6.91 (m, 3H), 6.78 (d, J = 2.0 Hz, 1H),
4.57 (dd, J = 7.2, 2.0 Hz, 1H), 4.00–3.95 (m, 1H), 3.74 (d, J = 10.4 Hz, 1H), 3.60 (s,
3H), 0.943–0.929 (m, 18H), 0.19 (d, J = 4.0 Hz, 6H), 0.14 (d, J = 8.4 Hz, 6H) ppm.
13C NMR (100 MHz, CDCl3) d = 201.2, 154.1, 152.5, 137.5, 130.6, 130.3, 123.3,
120.9, 118.7, 86.8, 78.4, 74.1, 60.3, 26.0, 25.9, 18.1, 18.0, ꢀ3.7, ꢀ4.0, ꢀ4.2,
ꢀ4.6 ppm. HRMS (ESI) calcd for C25H42O5Si2Na [(M+Na)+] 501.2463, found
1. Lee, I. K.; Lee, J. H.; Yun, B. S. Bioorg. Med. Chem. Lett. 2008, 18, 4566–4568.
2. Liu, Y.; Kubo, M.; Fukuyama, Y. J. Nat. Prod. 2012, 75, 2152–2157.
3. (a) Zhang, C.; Liu, J.; Du, Y. Tetrahedron Lett. 2013, 54, 3278–3280; (b) Cai, C.;
Liu, J.; Du, Y.; Linhardt, R. J. J. Org. Chem. 2010, 75, 5754–5756; (c) Du, Y.; Liu, J.;
Linhardt, R. J. J. Org. Chem. 2006, 71, 1251–1253; (d) Du, Y.; Chen, Q.; Linhardt,
R. J. J. Org. Chem. 2006, 71, 8446–8451; (e) Liu, J.; Du, Y.; Dong, X.; Meng, S.;
Xiao, J.; Cheng, L. Carbohydr. Res. 2006, 341, 2653–2657; (f) Chen, Q.; Du, Y.
Tetrahedron Lett. 2006, 47, 8489–8492.
4. (a) Ferrier, R. J. Chem. Rev. 1993, 93, 2779–2831; (b) Chida, N.; Ohtsuka, M.;
Nakazawa, K.; Ogawa, S. J. Org. Chem. 1991, 56, 2976–2983; (c) Bohno, M.;
Imase, H.; Chida, N. Chem. Commun. 2004, 1086–1087; (d) Tanimoto, H.; Saito,
R.; Chida, N. Tetrahedron Lett. 2008, 49, 358–362; (e) Urakawa, Y.; Sugimoto, T.;
Sato, H.; Ueda, M. Tetrahedron Lett. 2004, 45, 5885–5888; (f) Imuta, S.; Ochiai,
S.; Kuribayashi, M.; Chida, N. Tetrahedron Lett. 2003, 44, 5047–5051; (g)
Branchaud, B. P.; Friestad, G. K. Tetrahedron Lett. 1997, 38, 5933–5936.
5. Evans, M. E. Carbohydr. Res. 1972, 21, 4373–4375.
501.2472. Compound 18: ½a D22
ꢁ
ꢀ7.2 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3)
d = 8.14–8.10 (m, 1H), 7.57–7.53 (m, 1H), 7.44–7.37 (m, 2H), 4.97 (d, J = 5.2 Hz,
1H), 4.25 (dd, J = 7.2, 5.6 Hz, 1H), 3.76 (d, J = 7.2 Hz, 1H), 3.68 (s, 3H), 1.03 (s,
9H), 0.94 (s, 9H), 0.31 (d, J = 13.2 Hz, 6H), 0.18 (d, J = 5.6 Hz, 6H) ppm. 13C NMR
(100 MHz, CDCl3) d = 191.0, 166.8, 155.4, 125.7, 124.6, 123.2, 122.3, 114.6,
111.3, 85.6, 70.0, 60.2, 25.9, 25.8, 18.3, 18.0, ꢀ4.0, ꢀ4.1, ꢀ4.4, ꢀ4.5 ppm. HRMS
(ESI) calcd for C25H40O5Si2Na [(M+Na)+] 499.2306, found 499.2320. Ribisin A
(1): ½a 2D2
ꢁ
ꢀ23.3 (c 1, MeOH). 1H NMR (400 MHz, methonal-d4) d = 7.98 (dd,
J = 7.5, 1.2 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.41 (dt, J = 7.5, 1,4 Hz, 1H), 7.37 (dt,
J = 7.5, 1.2 Hz, 1H), 4.98 (d, J = 7.6 Hz, 1H), 4.03 (d, J = 10.0 Hz, 1H), 3.98 (dd,
J = 10.0, 7.2 Hz, 1H), 3.72 (s, 3H) ppm. 13C NMR (100 MHz, methonal-d4)
d = 193.1, 169.3, 157.4, 127.1, 125.9, 124.3, 122.8, 116.1, 112.7, 87.1, 78.8, 70.3,
6. (a) Grim, J. C.; Garber, K. C. A.; Kiessling, L. L. Org. Lett. 2011, 13, 3790–3793; (b)
Gurjar, M. K.; Yellol, G. S.; Mohapatra, D. K. Eur. J. Org. Chem. 2012, 1753–1758;
(c) Simao, A. C.; Silva, S.; Rauter, A. P.; Rollin, P.; Tatibouët, A. Eur. J. Org. Chem.
2011, 2286–2292.
60.8 ppm. HRMS (ESI) calcd for
271.0564.
C
13H12O5Na [(M+Na)+] 271.0577, found
7. (a) Takahashi, H.; Ikegami, S. Molecules 2005, 10, 901–911; (b) Iimori, T.;
Takahashi, H.; Ikegami, S. Tetrahedron Lett. 1996, 37, 649–652; (c) Chida, N.;