Synthesis of marchantin C, a novel microtubule inhibitor from liverworts

Article abstract of DOI:10.1016/j.tetlet.2010.03.125

Recently, remarkable microtubule inhibitor and anti-tumor activities of the bisbibenzyl marchantin C-isolated from liverworts like Marchantia polymorpha since 1983-were found. In this Letter we describe the first and efficient total synthesis of this subt

Full text of DOI:10.1016/j.tetlet.2010.03.125

Tetrahedron Letters 51 (2010) 2986–2989
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Synthesis of marchantin C, a novel microtubule inhibitor from liverworts
*
Andreas Speicher , Judith Holz
FR 8.1 Chemistry—Organic Chemistry, Saarland University, D-66041 Saarbrücken, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently, remarkable microtubule inhibitor and anti-tumor activities of the bisbibenzyl marchantin C—
isolated from liverworts like Marchantia polymorpha since 1983—were found. In this Letter we describe
the first and efficient total synthesis of this subtype of bisbibenzylic compounds with two biarylether
connections. The structure was confirmed by the spectroscopic data which were analyzed carefully to
exclude any errors in arene connection and substitution pattern.
Received 2 March 2010
Revised 24 March 2010
Accepted 30 March 2010
Available online 3 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Marchantin C
Bisbibenzyl
Total synthesis
Natural products
Liverwort constituents
Bisbibenzyls are acyclic or cyclic phenolic natural products that
are found exclusively in bryophytes.1 Biosynthetically, they origi-
nate from two units of the bibenzyl lunularin (2), which can be
combined by several modes of O–C and/or C–C attachment on
the basis of phenol oxidation coupling to different subtypes
(Scheme 1).2,3
OH
OH
OH
OH
H O
symmetrical
unsymmetrical
OH
C
O
+
C
C
H
O
O H
- 2 H
- 2 H
O
OH
H
O H
H
OH
3: isoperrottetin A
1: perrottetin E
2 (two molecules of lunularin)
6 x
C
O
3 x
6 x
C
C
O
C
9 x
C
C
"plagiochin/riccardin type"
HO HO
"isoplagiochin type"
"marchantin type"
OH
OH
OH
O
O
O
OH
OH
OH
OH
4: plagiochin E
5: marchantin C
6: isoplagiochin D
Scheme 1. Different subtypes of acyclic or cyclic bisbibenzyls.
* Corresponding author. Tel.: +49 681 302 2749; fax: +49 681 302 2029.
E-mail address: anspeich@mx.uni-saarland.de (A. Speicher).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.125

A. Speicher, J. Holz / Tetrahedron Letters 51 (2010) 2986–2989
2987
3-O
2'-C
3-O
6'-C
3-O
4'-C
OH
OR2
b
O
4'
O
6'
3
3
O
3
R
d
2'
OCH3
O
a
c
O
O
R
OH
OR1
OH
10: neomarchantin A
11: marchantin I
R = R1 = R2 = H: 5: marchantin C
R = R1 = H, R2 = CH3: 7: marchantin O
R = R2 = H, R1 = CH3: 8: marchantin P
R = OH, R1 = R2 = H: 9: marchantin B
HO
3'-O
OH
2
3'-O
4
OH
3'-O
6
3'
O
4
2
6
O
O
3'
3'
E
O
O
O
OH
OH
OH
12: isomarchantin C
13: riccardin B
14: ptychantol A
Figure 1. Different subtypes in the marchantin series.
From the acyclic precursors perrottetin E (1) with O–C connec-
tion and isoperrottetin A (3) with C–C connection, respectively, are
derived cyclic bisbibenzyls of the plagiochin/riccardin type like
plagiochin E (4), the marchantin type like marchantin C (5), or
the isoplagiochin type like isoplagiochin D (6) by a second O–C
or C–C connection. Not all possible subtypes were isolated yet from
bryophytes, for an overview see Ref. 4.
CHO
CHO
O
O
O
O
(i)
17
F
CHO
a
c
OMe
OH
(ii)
OH
O
OMe
OMe
16
15
18
In the marchantin series, six subtypes are possible by the sec-
ond O–C connection (Fig. 1). Unfortunately, the nomenclature for
these compounds is not standardized (plant source, historical as-
pects). Furthermore, derivatives containing additional hydroxyl
or methyl ether functionalities were also isolated or the parent
compound itself was not yet found.4 Marchantin C (5) represents
the 3-O?20-C cyclization type of 1 with no further modification
and was first isolated from Marchantia polymorpha, Marchantia
paleacea var. diterpa and Marchantia tosana5 and then from addi-
tional six different liverwort species.6–8 Its monomethylethers
were isolated as marchantin O (7)9,10 and P (8),11 the dimethyle-
ther, however was not yet found. It should further be mentioned,
that originally the dihydroxylated compound 9 was also named
marchantin C but later on was renamed marchantin B.5
OMe
OMe
OMe
b
RO
BnO
HO
(iv)
BnO
-BrPh3+P
(v)
OHC
21
R = H: 19
22
(iii)
R = Bn: 20
Scheme 2. Reaction conditions: (i) CH(OEt)3, tetrabutylammonium tribromide, 1,3-
propanediol, 50 °C, 2 h (91%); (ii) 16, K2CO3, DMF, 165 °C, 12 h (97%); (iii) BnBr,
K2CO3, THF, reflux, 12 h (95%); (iv) NaBH4, EtOH, 0 ° to rt, 12 h (92%); (v) PPh3ꢀHBr,
MeCN, 95 °C, 12 h (85%).
The following moderate biological activities were previously re-
ported for marchantin C (5): cytotoxic activity against KB cell lines,
anti-HIV-1 activity and DNA polymerase b inhibition,4,12 cytotoxic-
ity in the P388 assay and some antimicrobial activity against the
Gram-positive bacterium Bacillus subtilis and against Trichophyton
mentagrophyte,13 inhibition of lipopolysaccharide-induced nitric
Continuing our efforts on total syntheses of biological active liv-
erwort constituents especially of the bisbibenzyl type,20 we can
now report on a short and efficient total synthesis of marchantin
C (5) with subsequent construction of the a–b–c–d arene skeleton.
The c–a fragment 1821,22 is now obtained by a more straightfor-
ward sequence20 starting from isovanilline (15) and SNAr with 4-
fluorobenzaldehyde (17). The 1,2,3-trisubstituted segment b is pre-
pared as phosphonium salt 22 starting from o-vanilline 19 with O-
benzylation and reduction (Scheme 2).
Wittig reaction of 18 and 22 followed by hydrogenation gives
bibenzyl 23 with a free o,o0-disubstituted phenolic OH group. The
segment d is introduced by an Ullmann reaction of the phenol 23
with 3-bromo-benzaldehyde (24) yielding the acyclic precursor
25. After deprotection of the second aldehyde functionality (to
26), the dialdehyde is ring closed under McMurry conditions to
give the stilbene 27. Finally, the bisbibenzylic macrocycle is
oxide synthase (NOS) in RAW 264.7 macrophages,14 and
dase inhibitory activity.8
a-glucosi-
But more recently, macrocyclic bisbibenzyls especially of the
plagiochin/riccardin type and of the marchantin type are attracting
an enhanced attention due to new significant biological activi-
ties.15–17 Marchantin C (5) induces apoptosis of human glioma A
172 cells.18 Furthermore, it is a novel microtubule inhibitor with
anti-tumor activity both in vivo and in vitro.19 Surprisingly, 5 or
one of its methylether derivatives was never synthesized and only
small amounts from natural sources were used for testing.

2988
A. Speicher, J. Holz / Tetrahedron Letters 51 (2010) 2986–2989
OMe
b
OMe
OHC
Br
24
OHC
O
HO
d
b
d
a
(i), (ii)
O
O
O
O
18 + 22
(iv)
(iii)
a
c
c
O
O
25
23
OMe
OMe
OMe
OMe
OR
OHC
O
O
O
d
b
(v)
(vi)
CHO
c
a
O
O
O
26
OMe
OMe
OR
R = Me: 28
R = H: 5
27
(vii)
Scheme 3. Synthesis of marchantin C (5). Reagents and conditions: (i) K2CO3, 18-crown-6, CH2Cl2, reflux, 12 h (62%); (ii) H2, Pd/C, 3 bar, 24 h (98%); (iii) CuO, K2CO3, pyridine,
160 °C, 12 h (97%); (iv) 2 M HCl/THF, rt, 12 h (97%); (v) Zn, TiCl4, THF, ꢁ10 °C to reflux, 12 h (47%); (vi) H2, Pd/C, 3 bar, 24 h (96%); (vii) BBr3, CH2Cl2, ꢁ78 °C to rt, 12 h (85%).
Table 1
Table 2
1H NMR data of synthetic compounds 5 (see Fig. 2) and the published data for
marchantin C (400 MHz, CDCl3, d in ppm)
13C NMR data of synthetic compounds 5 and the published data for marchantin C
(100 MHz, CDCl3, d in ppm)
Synthetic 5
Natural product 523
Synthetic 5
Natural product 523
H-2
H-4
H-5
H-6
6.62 (dd, J = 2.3, 1.5 Hz)
6.54 (ddd, J = 8.0, 2.5, 0.8 Hz)
6.98 (t, J = 8.0 Hz)
6.37 (t, not resolved, J = 8.0 Hz)
2.75–2.78 (m)
2.83–2.86 (m)
5.53 (d, J = 2.0 Hz)
6.88 (d, J = 8.0 Hz)
6.73 (dd, J = 8.3, 2.0 Hz)
7.02 (dd, J = 7.8, 1.5 Hz)
7.15 (t, J = 7.8 Hz)
6.87 (dd, J = 8.0, 1.5 Hz)
2.97–3.04 (m)
6.62 (dd, J = 2.5, 1.5 Hz)
6.54 (ddd, J = 7.8, 2.5, 0.7 Hz)
6.98 (t, J = 7.8 Hz)
6.38 (ddd, J = 7.8, 1.5, 0.7 Hz)
2.75–2.86 (m)
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
143.0
115.6
156.8
112.0
128.9
123.3
35.83
34.00
132.7
115.5
146.1
143.5
115.0
122.4
148.7
139.7
136.2
122.0
126.0
114.4
30.34
35.34
139.1
129.6
121.3
152.9
142.6
115.4
156.8
111.9
128.6
122.9
35.5
H2-7
H2-8
H-10
H-13
H-14
H-40
H-50
H-60
H2-70
H2-80
H-100
H-110
5.52 (d, J = 2.0 Hz)
6.88 (d, J = 8.1 Hz)
6.74 (dd, J = 8.1, 2.0 Hz)
7.02 (dd, J = 7.8, 1.6 Hz)
7.15 (t, J = 7.8 Hz)
33.7
C-9
132.5
115.5
146.0
143.1
115.1
122.2
148.6
139.6
136.0
121.7
125.8
114.4
30.1
C-10
C-11
C-12
C-13
C-14
C-10
C-20
C-30
C-40
C-50
C-60
C-70
C-80
C-90
C-100
C-110
C-120
6.87 (dd, J = 7.8, 1.6 Hz)
2.97–3.03 (m)
6.94 (d, J = 8.5 Hz)
6.59 (d, J = 8.3 Hz)
6.94 (d, J = 8.5 Hz)
6.60 (d, J = 8.5 Hz)
OH
2
35.1
7
1'
3
O
7'
1
2'
3'
138.8
129.4
121.1
152.7
6'
5'
8
6
4
5
4'
10'
9
8'
14
13
10 11'
O
9'
10'
11
OH
12
11'
connection and substitution pattern20, the structure of 4 is strongly
verified by further NMR experiments (H,H COSY, C,H COSY,
HMBC).
a
b
Figure 2. (a) Molecule numbering for NMR correlation; (b) AM1 structure of 5.24
Acknowledgment
We thank the Deutsche Forschungsgemeinschaft for financial
support (DFG, Sp 498/2-1).
obtained by hydrogenation (to 28) and deprotection of the pheno-
lic OH groups yields compound 5 in 22% overall yield (six steps
from 18 and 22, Scheme 3).
References and notes
The molecular formula C28H24O4 is confirmed by HR-EI-MS; M+
peak at m/z = 424.1690 (calcd 424.1675). The spectroscopic data
(see Tables 1 and 2) match with those reported in the literature23
for the isolated marchantin C (5). To exclude any errors in arene
1. Asakawa, Y. In Progress in the Chemistry of Organic Natural Products; Herz, E.,
Kirby, G. W., Moore, R. E., Steglich, W., Tamm, Ch., Eds.; Springer: Wien-New
York, 1995; p 5.
2. Keserü, G. M.; Nógrádi, M. Phytochemistry 1992, 31, 1573–1576.

A. Speicher, J. Holz / Tetrahedron Letters 51 (2010) 2986–2989
2989
3. Friederich, S.; Rueffer, M.; Asakawa, Y.; Zenk, M. H. Phytochemistry 1999, 52,
1195–1202.
4. Asakawa, Y.; Toyota, M.; Tori, M.; Hashimoto, T. Spectroscopy 2000, 14, 149–175.
5. Asakawa, Y.; Toyota, M.; Matsuda, R.; Takikawa, R.; Takemoto, T.
Phytochemistry 1983, 22, 1413–1415.
16. Qu, J.; Xie, C.; Guo, H.; Yu, W.; Lou, H. Phytochemistry 2007, 68, 1767–1774.
17. Asakawa, Y.; Ludwiczuk, A.; Nagashima, F.; Toyota, M.; Hashimoto, T.; Tori, M.;
Fukuyama, Y.; Harinantenaina, L. Heterocycles 2009, 77, 99–150.
18. Shi, Y.-Q.; Liao, Y.-X.; Qu, X.-J.; Yuan, H.-Q.; Li, S.; Qu, J.-B.; Lou, H.-X. Cancer
Lett. 2008, 262, 173–182.
6. So, M. L.; Chan, W. H.; Xia, P. F.; Cui, Y. Nat. Prod. Lett. 2002, 16, 167–171.
7. Lu, Z.-Q.; Fan, P.-H.; Ji, M.; Lou, H.-X. J. Asian Nat. Prod. Res. 2006, 8, 187–192.
8. Harinantenaina, L.; Kida, S.; Asakawa, Y. ARKIVOC 2007, 22–29.
9. Wei, H.-C.; Ma, S.-J.; Wu, C.-L. Phytochemistry 1995, 39, 91–97.
10. Toyota, M.; Konoshima, M.; Asakawa, Y. Phytochemistry 1999, 52, 105–112.
11. Tori, M.; Aoki, M.; Asakawa, Y. Phytochemistry 1994, 36, 73–76.
12. Ref. 1, p. 464.
13. Scher, J. M.; Burgess, E. J.; Lorimer, S. D.; Perry, N. B. Tetrahedron 2002, 58,
7875–7882.
14. Harinantenaina, L.; Quang, D. N.; Takeshi, N.; Hashimoto, T.; Kohchi, C.; Soma,
G.-I.; Asakawa, Y. J. Nat. Prod. 2005, 68, 1779–1781.
19. Shi, Y.-Q.; Zhu, C.-J.; Yuan, H.-Q.; Li, B.-Q.; Gao, J.; Qu, X.-J.; Sun, B.; Cheng, Y.-
N.; Li, S.; Li, X.; Lou, H.-X. Cancer Lett. 2009, 276, 160–170.
20. Speicher, A.; Groh, M.; Zapp, J.; Schaumlöffel, A.; Knauer, M.; Bringmann, G.
Synlett 2009, 1852–1858.
21. Eicher, T.; Fey, S.; Puhl, W.; Büchel, E.; Speicher, A. Eur. J. Org. Chem. 1998, 877–
888.
22. Harrowven, D. C.; Woodcock, T. H.; Peter, D. Angew. Chem., Int. Ed. 2005, 44,
3967–3969.
23. Tori, M.; Toyota, M.; Harrison, L. J.; Takikawa, K.; Asakawa, Y. Tetrahedron Lett.
1985, 26, 4735–4738.
24. HyperChem™ Professional 7.52, Hypercube, Inc., 1115 NW 4th Street,
Gainesville, FL 32601, USA.
15. Niu, C.; Qu, J. B.; Lou, H. X. Chem. Biodivers. 2006, 3, 34–40.