Rapid synthesis of methoxyconidiol and conitriol stereoisomers

Article abstract of DOI:10.1016/j.tetlet.2012.06.050

We describe the diastereoselective synthesis of the marine meroterpenes methoxyconidiol and conitriol in their trans form from the readily available 1-bromo-2,5-dimethoxybenzene in only three steps. The choice of the protective group strategy influenced n

Full text of DOI:10.1016/j.tetlet.2012.06.050

Tetrahedron Letters 53 (2012) 4548–4550
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Rapid synthesis of methoxyconidiol and conitriol stereoisomers
⇑
Gérald Lopez , Anne Witczak, Christophe Menniti, Nicolas Inguimbert, Bernard Banaigs
Laboratoire de Chimie des Biomolécules et de l’Environnement, Université de Perpignan Via Domitia, 52 Av. Paul Alduy, 66860 Perpignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 March 2012
Revised 7 June 2012
Accepted 11 June 2012
Available online 16 June 2012
We describe the diastereoselective synthesis of the marine meroterpenes methoxyconidiol and conitriol
in their trans form from the readily available 1-bromo-2,5-dimethoxybenzene in only three steps. The
choice of the protective group strategy influenced not only the overall reaction yields but also the diaste-
reoisomeric ratio. In addition, we describe the synthesis of natural conitriol (cis form) for the first time.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Meroterpenes
Methoxyconidiol
Conitriol
Diastereoselective synthesis
The term meroterpenoids was initially proposed in 1968 by
Cornforth as ‘Compounds containing terpenoid elements along with
structures of different biosynthetic origin’.1 Many meroterpenes
have been characterized in both terrestrial and marine sources with
the terpenoid moiety ranging in size from one to nine isoprene
units. Concerning marine organisms, these compounds are mainly
found not only in brown algae2 but also in microorganisms3 and
invertebrates such as sponges,4 ascidians,5 or octocorals.6
epimers at C10. Conicol 7 was described to have a trans-diaxial rela-
tionship between H10 and H60, identical to tetrahydrocannabinol 8
another well-known natural diprenylated hydroquinone. The pres-
ence of both stereoisomers conidiol and epiconicol in the same
species Aplidium conicum indicates that the C10–C60 cyclization to
the a-terpineol six-membered ring lacks stereospecificity.
Primary screening has shown that methoxyconidiol has a
moderate antiproliferative activity against bacteria.8 We further
demonstrated that methoxyconidiol 3 presents an antimitotic ac-
tion on the first division of sea urchin embryos.10 The results of this
study suggested that the mechanism of the action of methoxyconi-
diol might be mediated by disruption of microtubule dynamics.
These promising results led us to synthesize methoxyconidiol
together with epiconicol and didehydroconicol.11 The diastereose-
lective synthesis of methoxyconidiol 3 with the cis orientation of
Among ascidians, the genus Aplidium was found to produce a
variety of diprenylated hydroquinone derivatives with a range of
structural diversity generated by cyclization between hydroqui-
none and terpene parts and/or within the two isoprenoid units.
The bicyclic or tricyclic systems obtained are formed via the com-
mon intermediate geranylhydroquinone 1 which is also isolated
from an Aplidium species, Aplidium antillense.7 Some of these
meroterpenes were described to possess moderate antibacterial
and antiproliferative activities but they were often tested as race-
mic mixtures.
1
OH
1
OH
O
7'
10'
We reported8 the isolation and structural elucidation of the new
meroterpenes methoxyconidiol 3 and didehydroconicol 5, together
with the known compounds cordiachromene 2 and epiconicol 4,9
extracted from a colonial ascidian Aplidium aff. densum. In this ser-
(R)
1'
3'
2
HO
2
6'
1'
(S)
HO
6'
7'
RO
Cordiachromene [2]
OH
Geranylhydroquinone [1]
R = CH3 Methoxyconidiol [3]
R = H Conitriol [6]
ies (Fig. 1), the relative stereochemistry of both a-terpineol deriv-
atives 38 and 69 was assumed to be the same with a cis orientation
of H10 and H60 protons whereas the chromenes 4 and 7 are two
O
O
1
7'
O
H
(S)
6'
HO
6'
(R)
1'
3
(R)
1'
H
OH
H
3'
HO
10'
⇑
Corresponding author. Tel.: +33 468662074; fax: +33 430198138.
E-mail addresses: gerald.lopez@enscm.fr (G. Lopez), banaigs@univ-perp.fr (B.
Banaigs).
H-1'α Epiconicol [4]
H-1'β Conicol [7]
Didehydroconicol [5]
Tetrahydrocannabinol [8]
Present address: Institut Charles Gerhardt - Ingénierie et Architectures Macro-
moléculaires (IAM), École Nationale Supérieure de Chimie de Montpellier - 8, Rue de
l’École Normale, 34296 Montpellier Cedex, France. Tel.: +33 467144336.
Figure 1. Structures of natural meroterpenes isolated from ascidians of the genus
Aplidium. Configurations indicated for C10 and C60 in compounds 3, 6, 4, and 7 are
relative configurations.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.050

G. Lopez et al. / Tetrahedron Letters 53 (2012) 4548–4550
4549
c
d
d
[11] R=H
[13] R=H
cis/trans 20/80
cis/trans 15/85
OH
OH
MeO
OMe
MeO
OH
Br
a
H
H
OR
OR
OMe
OMe
b
[12] R=Me
cis/trans 15/85
OMe
[14] R=Me
cis/trans 10/90
[9]
[10]
Scheme 1. Diastereoselective synthesis of trans-methoxyconidiol 14 and trans-conitriol 13. Configurations indicated in compounds 11, 12, 13, and 14 are relative
configurations. Reagents and conditions: (a) (i) n-BuLi, Et2O, ꢀ78 °C, 1 h, (ii) citral, ꢀ78 °C to rt, 1 h; 85%, (b) AcCl/MeOH, rt, 12 h; 73%, (c) HCl 12 M, THF, rt, 12 h; 82%, (d) (i)
CAN, CH3CN/H2O:1/1, rt, 15 min, (ii) Na2S2O4/H2O, THF, 15 min; 85%.
H10 and H60 protons was achieved in three steps from 4-hydroxy-
phenol: (i) protection of the aromatic hydroxyl group as methoxy-
methyl ethers (ii) aromatic lithiation followed by the addition of
citral (iii) acidic treatment affording the 6-membered ring by intra-
molecular cyclization.
Here we report, for the first time, the synthesis of conitriol 6 and
a new and short diastereoselective synthesis toward the trans iso-
mers of methoxyconidiol and conitriol.
trans-Methoxyconidiol and trans-conitriol were synthesized, as
pairs of enantiomers, starting from commercially available 1-bro-
mo-2,5-dimethoxybenzene 9 (Scheme 1). Firstly, a bromine-lith-
ium exchange12 followed by the addition of citral (E-geranial/
Z-neral 1/1)13 afforded the alcohol 1014 in 85% yield (Z/E 30/70).
The subsequent acidification of the product with either aqueous
HCl (path c) or methanolic HCl (path b) resulted in the formation
of the desired 6-membered ring 1114 (cis/trans 20/80) and 1214
(cis/trans 15/85) in 82% and 73% yield, respectively. Finally, the
oxidation-reduction sequence with ceric ammonium nitrate
Figure 2. An energy-minimized structure20 of cis- and trans-methoxyconidiol
(CAN)15 followed by treatment with sodium dithionite (Na2S2O4)
showing the dihedral angles21 between H10 and H60 along with the orientation of
C90 in relation with the aromatic ring. Indicated configurations are relative.
afforded the deprotected 4-hydroxyphenolic products trans-conit-
riol 1316 (cis/trans 15/85) and trans-methoxyconidiol 1417 (cis/
trans 10/90) both in 85% yield.
trans-Methoxyconidiol 14 was obtained as an isomeric mixture
in 52% overall yield as a white powder with a molecular formula of
We postulated that the formation of the 6-membered rings 11
and 12 involved OH-protonation followed by water elimination
to give the a-terpinyl tertiary carbocation stabilized by a benzyl/al-
lyl effect. The transient carbocation was then trapped by nucleo-
philes such as water (path c) or methanol (path b) forming the
C
17H24O3 confirmed by HRMS. The 1H NMR spectroscopic data
3
0
0
showed a coupling constant J1 ,6 value of 1 Hz indicating a trans
relationship between the H10 and the H60 protons. By contrast,
the vicinal coupling constant in cis-methoxyconidiol was found
to be 4.6 Hz.8 Moreover, the 90 methyl group appeared at d
0.78 ppm, which was downfield compared to the previously
reported chemical shift of d 0.54 ppm. This was presumably caused
by a weaker interaction between the 90 methyl group and the
dimethoxybenzene
a-terpineol derivatives 11 (cis/trans 20/80)
and 12 (cis/trans 15/85).
The alcohol 10 is a mixture of Z (nerol-methoxyhydroquinone)
and E (geraniol-methoxyhydroquinone) isomers (Z/E 30/70). The
C20–C30 double bond of nerol-methoxyhydroquinone has the same
Z configuration as that of trans-conitriol but not geraniol-methoxy-
hydroquinone, which represents 70% of the starting mixture. We
propose that trans-conitriol (or trans-methoxyconidiol) is formed
via a common intermediate, the stabilized benzylic/allylic cation,
in the reactions of both Z- and E-isomers of alcohol 10 (Scheme
hydroquinone ring’s
p
-cloud in the trans configuration (Fig. 2).19
Finally, in the 1H NMR spectrum of the mixture of the methoxy-
conidiol diastereoisomers, a major sharp singlet attributed to
4-OH of the trans isomer was found at d 8.46 ppm and a minor sin-
glet attributing to 4-OH of the cis isomer was found at d 4.05 ppm
(90:10 ratio), the later was consistent with the 4-OH found at d
4.27 ppm in the 1H NMR of methoxyconidiol isolated from Aplidi-
um aff. densum.8 All these singlets disappeared when a deuterium
exchange experiment was performed.
2). This intermediate was suggested for the biosynthesis of D1
THCA by
1-THCA synthase.21
-
D
This mechanism can explain the 10–60 cyclization but not the
diastereoselective ratio in favor of the trans configuration. Indeed,
we obtained preferentially the cis isomer (cis/trans 80/20) in the
synthesis of methoxyconidiol described precedently.11 The diaste-
reoisomeric ratio is completely reversed in the strategy described
here for the synthesis of trans-methoxyconidiol (cis/trans 10/90).
In the same way, with the first synthesis protocol we obtained
preferentially conitriol (cis/trans 80/20)18 whereas trans-conitriol
was prepared with high diastereoselectivity (cis/trans 15/85) with
the protocol described here. The role of parameters that can
influence conformational mobility of the isoprenic chain such as
the protecting group (methoxy vs methoxymethyl) or E/Z ratio in
alcohol 10, together with work-up procedure, toward the diastere-
oselectivity cis/trans is still under investigation regarding stereo-
chemical outcome of the reaction.
trans-Conitriol 13 was obtained as a colorless oil with a molec-
ular formula of C16H22O3 confirmed by HRMS. The 1H NMR spec-
troscopy16 enabled us to prove again
a trans relationship
between H10 and H60, in contrast with conitriol 6 previously char-
acterized by Salvà and collaborators.9 As for trans-methoxyconi-
3
0
0
diol, the trans relationship was supported by the J1 ,6 coupling
constant value of 1 Hz together with the chemical shift of the sharp
singlet attributed to 4-OH at d 8.53 ppm.
In addition, we also synthesized cis-conitriol for the first time.18
The compound was obtained as a colorless oil following the proto-
col we described in Ref. 11,18. All the spectroscopic data were
identical with those previously published for the natural product.9

4550
G. Lopez et al. / Tetrahedron Letters 53 (2012) 4548–4550
MeO
OH
OMe
MeO
MeO
MeO
MeO
H+
1'
H2O
- H+
6'-1'-closure
1'
1'
1'
6'
6'
6'
6'
OH
H
H
- H2O
MeO
HO
OMe
OMe
OMe
OMe
α-terpenyl cation
trans-conitriol
OMe
Scheme 2. Postulated mechanism accounting for the formation of trans-conitriol 13.
313.1780 (Calcd), 313.1774 (Found). Data for major product trans-11 1H NMR
(DMSO-d6, 400 MHz) d (ppm): 6.96 (s, 1H, H-3), 6.77 (m, 2H, H-5 H-6); 5.37 (s,
In conclusion, we have described an efficient route for the syn-
thesis of the meroterpenes trans-methoxyconidiol 14 and trans-
conitriol 13 previously isolated from Ascidian species as their cis
form. It should be noted that, to the best of our knowledge, the syn-
thesis of conitriol is described for the first time in this article. With
the synthetic method presented here compounds 13 and 14 were
obtained in high yields in less than 12 h, at room temperature,
without any side products and with a high diastereoselectivity.
1H, H-20); 4.64 (s, 1H, 70-OH); 3.82 (s, 6H, 1-OMe 4-OMe); 3.23 (d, 1H, H-10,
3
J1 ,6 = 1.25 Hz); 2.31 (d, 1H, H-60); 2.12–1.51 (m, 4H, H-40 H-50); 1.82 (s, 3H, H-
100); 1.24 (s, 6H, H-80 H-90). 13C NMR (DMSO-d6, 100 MHz) d (ppm): 152.7 (C-
4), 148.5 (C-1), 135.3 (C-30), 126.4 (C-2), 123.9 (C-20), 116.0 (C-3), 112.0 (C-5 C-
6), 70.6 (C-70), 55.9 (1-OMe 4-OMe), 45.6 (C-60), 31.5 (C-40), 28.0 (C-80 C-90),
26.4 (C-10), 24.9 (C-50), 22.3 (C-100). HRMS ESI+: (C18H26O3+Na)+: 313.1780
(Calcd), 313.1777 (Found). Data for major product trans-12 1H NMR (DMSO-d6,
400 MHz) d (ppm): 6.95 (s, 1H, H-3); 6.75 (m, 2H, H-5 H-6); 5.80 (s, 1H, H-20);
0
0
3.83 (s, 6H, 1-OMe 4-OMe); 3.31 (s, 3H, 70-OMe); 3.21 (d, 1H, H-10,
3
J1 ,6 = 1.43 Hz); 2.33 (d, 1H, H-60); 2.10–1.52 (m, 4H, H-40 H-50); 1.80 (s, 3H,
H-100); 1.23 (s, 6H, H-80 H-90). 13C NMR (DMSO-d6, 100 MHz) d (ppm): 152.6
(C-4), 148.6 (C-1), 134.8 (C-30), 132.1 (C-2), 124.4 (C-20), 118.5 (C-3), 111.0 (C-5
C-6), 77.1 (C-70), 55.6 (1-OMe 4-OMe), 45.1 (70-OMe), 36.1 (C-60), 31.1 (C-40),
23.7 (C-80 C-90), 23.0 (C-10 C-50), 22.9 (C-100). HRMS ESI+: (C19H28O3+Na)+:
327.1936 (Calcd), 327.1943 (Found).
0
0
Acknowledgments
G.L. would like to thank Dr. Nabyl Merbouh and Mrs. Liu-Lopez
Fang for their useful comments on the manuscript. This work is
part of the ECIMAR (ANR-06-BDIV-001-04) project granted by the
Agence Nationale de la Recherche (ANR).
15. Luly, J. R.; Rapoport, H. J. Org. Chem. 1981, 46, 2745–2752.
16. Data for major product trans-13 1H NMR (CDCl3, 400 MHz) d (ppm): 8.65 (s, 1H,
1-OH); 8.53 (s, 1H, 4-OH); 6.55–6.50 (m, 3H, H-3 H-5 H-6); 5.35 (s, 1H, H-20);
3
4.50 (s, 1H, 70-OH); 3.90 (d, 1H, H-10, J1 ,6 = 1 Hz); 2.10 (s, 1H, H-40); 2.02 (d,
1H, H-60); 1.82 (s, 3H, H-100); 1.65 (s, 1H, H-50); 1.24 (s, 3H, H-80); 0.98 (s, 3H,
H-90). 13C NMR (CDCl3, 100 MHz) d (ppm): 149.1 (C-4), 148.1 (C-1), 134.2 (C-
30), 128.1 (C-2), 124.1 (C-20), 118.3 (C-3), 116.0 (C-5 C-6), 73.5 (C-70), 46.2 (C-
60), 33.1 (C-10), 30.5 (C-40), 29.3(C-80); 23.2 (C-90); 22.5 (C-100), 20.6 (C-50).
HRMS ESI+: (C16H22O3+Na)+: 285.1467 (Calcd), 285.1475 (Found). Data for
minor product cis-6: see Ref. 9.
0
0
References and notes
1. Cornforth, J. W. Chem. Br. 1968, 4, 102–106.
2. Jung, M.; Jang, K. H.; Kim, B.; Lee, B. H.; Wook, B.; Oh, K.-B.; Shin, J. J. Nat. Prod.
2008, 71, 1714–1719.
3. Cueto, M.; MacMillan, J. B.; Jensen, P. R.; Fenical, W. Phytochemistry 2006, 67,
1826–1831.
4. Zhang, W.; Khalil, Z. G.; Capon, R. J. Tetrahedron 1985, 67, 2591–2595.
5. Appleton, D. R.; Chuen, C. S.; Berridge, M. V.; Webb, V. L.; Copp, B. R. J. Org.
Chem. 2009, 74, 9195–9198.
6. Sheu, J. H.; Su, J. H.; Sung, P. J.; Wang, G. H.; Dai, C. F. J. Nat. Prod. 2004, 67,
2048–2052.
7. Benslimane, A. F.; Pouchus, Y. F.; Le Boterff, J.; Verbist, J. F.; Roussakis, C.;
Monniot, F. J. Nat. Prod. 1988, 51, 582–583.
8. Simon-Levert, A.; Arrault, A.; Bontemps-Subielos, N.; Canal, C.; Banaigs, B. J.
Nat. Prod. 2005, 68, 1412–1415.
9. Garrido, L.; Zubia, E.; Ortega, M. J.; Salvà, J. J. Nat. Prod. 2002, 6, 1328–1331.
10. Simon-Levert, A.; Azeb, A.; Bontemps-Subielos, N.; Banaigs, B.; Genevière, A. M.
Chem. Biol. Interact. 2007, 168, 106–116.
11. Simon-Levert, A.; Menniti, C.; Soulère, L.; Genevière, A. M.; Barthomeuf, C.;
Banaigs, B.; Witczak, A. Marine Drugs 2010, 8, 347–358.
12. Carreno, M. C.; Ruano, J. L. G.; Toledo, M. A.; Urbano, A. Tetrahedron: Asymmetry
1997, 8, 913–921.
13. Li, S.; Chiu, P. Tetrahedron Lett. 2008, 49, 1741–1744.
14. All new compounds were fully characterized on the basis of 1H NMR, 13C NMR,
and mass spectroscopic data. Data for major product (E)-10 1H NMR (CDCl3,
400 MHz) d (ppm): 7.03 (s, 1H, H-3); 6,81 (m, 2H, H-5 H-6); 5.80 (d,1H, H-20);
5.20 (m, 2H, H-10 H-60); 3.83 (s, 6H, 1-OMe 4-OMe); 2.00 (m, 3H, H-40 H-50 10-
OH); 1.83–1.80 (m, 9H, 80-CH3 80-CH3 90-CH3). 13C NMR (CDCl3, 100 MHz) d
(ppm): 153.9 (C-4), 151.3 (C-1), 137.0 (C-30), 130.8 (C-70), 127.1 (C-2), 125.0 (C-
60), 121.5 (C-20), 112.0 (C-3 C-5 C-6), 72,6 (C-10), 55,0 (1-OMe 4-OMe), 42,6 (C-
40), 24,6 (C-50), 22,6 (C-80 C-90), 16,4 (C-100). HRMS ESI+: (C18H26O3+Na)+:
17. Data for major product trans-14 1H NMR (CDCl3, 400 MHz) d (ppm): 8.55 (s, 1H,
1-OH); 8.46 (s, 1H, 4-OH); 6.58–6.52 (m, 3H, H-3 H-5 H-6); 5.90 (s, 1H, H-20);
3
3.76 (d, 1H, H-10, J1 ,6 = 1.11 Hz); 3.13 (s, 3H, 70-OMe); 2.12 (s, 1H, H-40); 2.10
(d, 1H, H-60); 1.69 (s, 3H, H-100); 1.63 (s, 1H, H-50); 0.89 (s, 3H, H-80); 0.78 (s,
3H, H-90). 13C NMR (CDCl3, 100 MHz) d (ppm): 152.1 (C-4), 147.9 (C-1), 131.2
(C-30), 128.1 (C-2), 125.2 (C-20), 119.3 (C-3), 115.0 (C-5 C-6), 77.5 (C-70), 48.0
(70-OMe), 45.2 (C-60), 33.1 (C-10), 30.5 (C-40), 22.0 (C-80 C-100), 20.9 (C-50), 19.5
(C-90). HRMS ESI+: (C17H24O3+Na)+: 299.1623 (Calcd), 299.1629 (Found). Data
for minor product cis-3: see Ref. 8.
0
0
18. For the first and the second steps of the synthesis, see Ref. 11. Typical procedure
for the third step: to a stirred solution of 1-[2,5-bis(methoxymethyloxy)phenyl]-
3,7-dimethyl-2,6-octadien-1-ol (0.1 g, 0.28 mmol) in THF/H2O (2:1, 10 mL) was
added dropwise 12 N hydrochloric acid (1.6 mL). The mixture was stirred at 8 °C
for 18 h then concentrated in vacuo. The crude was diluted with CH2Cl2 (10 mL),
washed with water (2 ꢁ 10 mL), dried (Na2SO4), and concentrated. The residue
was purified by silica gel chromatography (heptane/ethyl acetate, 7:3) to give
conitriol as a colorless oil (15 mg, 20%).
19. The energy-minimized structures were computed using the following
software: Avogadro: an open-source molecular builder and visualization tool.
Mac OS X Version 1.0.1 http://avogadro.openmolecules.net.
20. The dihedral angles values were determined in silico using the Avogadro
software. The estimated 3J values were obtained from the dihedral angles
values using the following software: Sweet J: a desktop calculator for the
Karplus equation. Mac OS X Version 2.2; http://www.inmr.net/sweetj.html.
21. Taura, F.; Morimoto, S.; Shoyama, Y. J. Am. Chem. Soc. 1995, 117, 9766–9767.