Total synthesis of cimiracemate B and analogs

Article abstract of DOI:10.1016/j.tet.2005.03.074

The synthesis of the biologically active cimiracemate B and some analogs is described. The key step of the synthesis is a coupling between a bromoketone and a cinnamic acid derivative.

Full text of DOI:10.1016/j.tet.2005.03.074

Tetrahedron 61 (2005) 5261–5266
Total synthesis of cimiracemate B and analogs
*
Fabienne Fache, Nicolas Suzan and Olivier Piva
*
´ ` ˆ
Universite Claude Bernard Lyon I, UMR CNRS 5181, Laboratoire de Chimie Organique, Photochimie et Synthese, Bat. Raulin,
43 bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
Received 25 January 2005; accepted 21 March 2005
Available online 7 April 2005
Abstract—The synthesis of the biologically active cimiracemate B and some analogs is described. The key step of the synthesis is a coupling
between a bromoketone and a cinnamic acid derivative.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
biological activities, reasonable amount of these products
need to be synthesized. To our knowledge, the total
synthesis of cimiracemates has not been reported to date.
Only one synthesis10 of petasiphenol, an anti mutagen
compound isolated from Petasites japonicum (Fig. 1) with a
structure close to cimiracemate B was described in 1992.
We report herein a straightforward access to cimiracemate
B and analogs starting from inexpensive commercial
eugenol and different cinnamic acids bearing hydroxy- or
methoxy groups on various positions on the aromatic ring.
Naturally occurring compounds possessing a 1,7-diaryl
skeleton have been widely described and present significant
biological activities1 (Fig. 1).
For example, curcumin, a natural pigment isolated from
Curcuma longa has been reported to inhibit growth of
several types of malignant cells2 and more particularly in
the case of HIV infection.3 Yakuchinone B extracted4 from
the seeds of Alpina oxyphylla is active against hyper-
cholesterolemia and atherosclerosis.5 Cimiracemates,
phenylpropanoic acid esters isolated6 from the rhizome of
Cimifuga racemosa are used in traditional medicine to treat
menopausal symptoms7 and inflammation.8 Recent studies9
have shown that they could have additional health benefits
as reactive oxygen species scavengers. Nevertheless, they
are produced in very few amounts as they represented,
respectively, 0.001% for cimiracemate A and 0.0006% for
cimiracemate B of the dry weight of the methanolic extract.9
Therefore, to go further in the search for other potential
2. Results and discussion
Two retrosyntheses have been considered (Fig. 2). The first
was based on the obvious esterification of a cinnamic acid 1
with an appropriate primary alcohol 2, the second required a
coupling between the carboxylate salt of the same acid 1
with a compound bearing a good leaving group typically a
tosylate or a bromide (3) which could be activated by the
presence of a suitable keto group in a-position.
Figure 1. Some natural diaryl biologically active molecules.
Keywords: Phenylpropanoic acid; Cimifuga racemosa; Cimiracemate B; Synthesis.
*
Corresponding authors. Tel.: C33 472 44 85 21; fax: 33 472 44 81 36; e-mail addresses: fache@univ-lyon1.fr; piva@univ-lyon1.fr
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.074

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F. Fache et al. / Tetrahedron 61 (2005) 5261–5266
Commercially available eugenol 4a was converted into
catechol 4b by treatment with n-Bu4NI and BCl3 as
described by Brooks et al.11 This reaction was stopped
before complete conversion (50%) but afforded the
expected catechol as the only new and easily isolated
compound (40%). Unfortunately, the direct hydroxybroma-
tion of both phenols 4a and 4b led to a complex mixture of
products and low yields of the expected bromohydrins.
Therefore, these compounds were protected as TBDMS
ethers, which were expected to resist to moderate acidic
conditions. While Fukami et al.10 used during the synthesis
of petasiphenol the ring opening of an epoxide by HBr to
obtain the corresponding bromohydrin, we chose alterna-
tively the direct hydroxybromation promoted by NBS in
aqueous DMSO12 which seems more suitable to avoid the
cleavage of the protecting groups of 5a and 5b (Fig. 3). Dess
Martin oxidation13 delivered ketones 3a and 3b in
acceptable yields while oxidation with PCC, PDC or
Swern conditions were less efficient. The coupling between
acids 1a–d and ketones 3a or 3b was achieved under phase
transfer catalysis and led to the protected cimiracemate
analogs 9a–g in good yields. Finally, deprotection of the
silylethers was not a trivial step. The classically used
nBu4NF method led in our case to complex mixtures and
low isolated yields. This surprising reactivity could be due
to the presence of the ketone which could easily be
deprotonated by this reagent.14 Aqueous HF in acetonitrile
was more efficient. The low to moderate isolated yields
(10–45%) obtained could be attributed to the great affinity
of polyphenols 10a–g for water.
Figure 2. Retrosynthetic analysis.
To have a rapid access to the target molecule, a direct
esterification of the a,b-unsaturated acid 1 with the primary
hydroxyl group of diol 2 was first investigated. Dihydroxyl-
ation of silylated eugenol 5a afforded the corresponding diol
2a in an acceptable yield. However, coupling of this
compound with cinnamic acid 1d under DCC activation
gave very disappointing results. The reaction led to a
complex mixture of mono- and diester without control of the
regioselectivity. Therefore, we explored an alternative
strategy based on the coupling between a bromoketone
and a carboxylate. By this way, the moderate nucleo-
philicity of the carboxylic group could be balanced by the
activation of the leaving group of the bromoketone.
Figure 3. (a) TBDMSCl, imidazole, DMAP, CH2Cl2 (b) NBS, H2O, DMSO, 0 8C (c) Dess–Martin oxidation (d) THF, MeOH, K2CO3 (e) n-Bu4NBr, toluene,
NaOHaq (f) at 0 8C HFaq, CH3CN, then NaOH.

F. Fache et al. / Tetrahedron 61 (2005) 5261–5266
5263
3. Conclusion
silica gel (petroleum ether/ethyl acetate 3:1) to give the
bisphenol 4b (183 mg, 1.22 mmol, 40% isolated yield) as an
oil.17 40% of the starting material were recovered.
In conclusion, we have described in this paper a simple and
straightforward synthesis of cimiracemate B and some
analogs. The possibility of varying the substituents on both
reagents makes this approach general. These new products
will be tested widely and some works are already in progress
1H NMR (300 MHz, CDCl3) d 3.27 (d, JZ6.9 Hz, 2H), 5.06
(m, 2H), 5.56 (m, OH), 5.94 (m, 1H), 6.71 (m, 3H); 13C
NMR (75 MHz, CDCl3) d 39.9 (CH2), 115.7 (CH]CH2),
115.9 (CH]CH2), 116.1 (CH), 121.3 (CH), 133.6 (C),
138.1 (CH), 142.1 (C), 143.9 (C).
`
in that perspective with the Chimiotheque Nationale of the
CNRS.
4.2.3. 3-(3,4-Di-t-butyldimethylsilyloxy)phenyl propene
5b. According to the general procedure from 4b: isolated
yield 63%; colourless oil; H NMR (300 MHz, CDCl3) d
0.18 (s, 12H), 0.98 (s, 18H), 3.25 (d, JZ6.4 Hz, 2H), 5.01
(m, 1H), 5.05 (m, 1H), 5.92 (m, 1H), 6.64 (m, 2H), 6.74 (d,
JZ7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d K3.7 (CH3–
Si), 18.8 (C), 26.3 (CH3), 39.8 (CH2), 115.7 (CH]CH2),
121.2 (CH), 121.7 (CH), 121.8 (CH), 133.4 (C), 138.2 (CH),
145.4 (C), 150.0 (C).
4. Experimental
4.1. General
1
Melting points were measured with a Bu¨chi melting point
apparatus. IR spectra were recorded on a Perkin Elmer
‘spectrum one’ spectrometer. NMR spectra were recorded
on a Bruker AC 300 spectrometer. Mass spectra were
recorded on a Finigan-MAT 95 XL instrument. Column
chromatography was carried out with silica gel 60 A
40–63 mm (SDS). Analytical thin layer chromatography was
performed on Merck Kieselgel 60F254 0.25 mm thickness
plates.
In the case of acid phenol derivatives, the presence of the
acid function has to be taken into account to evaluate the
quantities of imidazole, DMAP and TBDMSCl.
4.2.4. Protected 3-methoxy-4-hydroxycinnamic acid 8a.
According to the general procedure from 7a: isolated yield
4.2. General procedure for the silylation15 of phenol
derivatives with t-butyldimethylsilyl chloride
(TBDMSCl)
1
90%; H NMR (300 MHz, CDCl3) d 0.17 (s, 6H), 0.32 (s,
6H), 0.99 (s, 18H), 3.84 (s, 3H), 6.27 (d, JZ15.5 Hz, 1H),
6.92 (m, 3H), 7.55 (d, JZ15.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d K4.2 (CH3–Si), 18.2 (C), 18.9 (C), 26.0 (CH3),
55.8 (OCH3), 111.2 (CH), 118.12 (CH), 121.4 (CH), 122.7
(CH), 128.7 (C), 145.6 (CH), 147.9 (C), 151.6 (C), 167.5
(C]O).
Under nitrogen, to a stirred solution of phenol derivative
(1 equiv/OH), imidazole (1.1 equiv/OH) and DMAP
(0.15 equiv/OH) in CH2Cl2 (6.5 M) were added at 0 8C
1.1 equiv/OH of TBDMSCl. The solution was allowed to
return to room temperature and was stirred until the reaction
was finished. After addition of NH4Cl, the reaction mixture
was extracted three times with CH2Cl2 and dried over
MgSO4. The organic phase was concentrated and the
residue purified by flash column chromatography on silica
gel (petroleum ether/ethyl acetate 9:1) to give the desired
protected phenol.
4.2.5. Protected coumaric acid 8b. According to the
general procedure from 7b: isolated yield 67%;18 1H NMR
(300 MHz, CDCl3) d 0.22 (s, 6H), 0.32 (s, 6H), 0.98 (s,
18H), 6.27 (d, JZ15.5 Hz, 1H), 6.84 (d, JZ8.5 Hz, 2H),
7.40 (d, JZ8.5 Hz, 2H), 7.57 (d, JZ15.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) d: K4.3 and K4.0 (CH3–Si), 18.1
and 18.6 (C), 25.96 and 26.04 (CH3), 118.1 (CH), 120.8
(CH), 128.1 (C), 130.0 (CH), 145.2 (CH), 158.1 (C), 167.6
(C]O).
4.2.1. Protected eugenol 5a. According to the general
procedure from 4a: isolated yield 90%; colourless oil16; IR
(neat) 2930, 1514, 1260, 1155, 1126, 1041, 889, 840 cmK1
;
1H NMR (300 MHz, CDCl3) d 0.21 (s, 6H), 1.06 (s, 9H),
3.37 (d, JZ6.4 Hz, 2H), 3.83 (s, 3H), 5.09 (m, 1H), 5.13 (m,
1H), 6.01 (m, 1H), 6.70 (m, 2H), 6.82 (d, JZ7.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) d K4.17 (CH3–Si), 19.8 (C),
26.2 (CH3), 40.4 (CH2), 55.9 (OCH3), 113.1 (CH]CH2),
115.9 (CH]CH2), 121.1 (CH), 121.2 (CH), 133.9 (C),
138.3 (CH), 143.7 (C), 151.2 (C).
4.3. General procedure for the bromohydrin synthesis12
To a stirred solution of alkene in H2O (2 equiv)/DMSO:
5/95 was added at 0 8C 1.1 equiv of freshly recrystallized
NBS. The reaction was monitored by TLC. At the end of the
reaction, the mixture was hydrolyzed with NaHCO3 (10%),
extracted with Et2O and dried over MgSO4. After filtration
and concentration, the crude product was purified by flash
column chromatography on silica gel (petroleum ether/ethyl
acetate 85:15) to give the desired bromohydrin as an oil.
4.2.2. 4-Propenyl-catechol 4b. Under nitrogen,11 to a
stirred solution of eugenol 4a (0.5 g, 3.05 mmol) in 9 mL of
dry CH2Cl2 was added anhydrous nBu4NI (1.24 g,
3.35 mmol). Then at 5 8C, 3.35 mL of BCl3 in CH2Cl2
(1 M) were added. The reaction mixture stood for 2 h
stirring at 5 8C and then was hydrolyzed by 10 mL of iced
water. After 15 min, a saturated aqueous solution of
NaHCO3 was added and the extraction was performed
with CH2Cl2. After drying of the organic phase with
MgSO4, filtration and evaporation of CH2Cl2, the crude
product was purified by flash column chromatography on
Some deprotection of the silylether was noticed and the
corresponding bromohydrin was also isolated. It could be
also silylated to improve the isolated yields of 5 and 6.
4.3.1.
1-Bromo-2-hydroxy-3-(3-methoxy-4-t-butyl-
dimethylsilyloxy)phenyl propane 6a. According to the
general procedure from 5a: 78% isolated yield; 1H
NMR (300 MHz, CDCl3) d 0.14 (s, 6H), 0.99 (s, 9H), 2.83

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F. Fache et al. / Tetrahedron 61 (2005) 5261–5266
(d, JZ6.6 Hz, 2H), 3.38 (dd, JZ10.5 Hz, JZ6 Hz, 1H),
3.49 (dd, JZ10.5 Hz, JZ4.1 Hz, 1H), 3.79 (s, 3H), 3.99 (m,
1H), 6.70 (m, 2H), 6.78 (d, JZ7.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d: K4.2 (CH3–Si), 18.8 (C), 26.1 (CH3),
39.5 (CH2), 41.5 (CH2), 55.9 (CH3), 72.2 (CH), 113.6 (CH),
121.4 (CH), 121.9 (CH), 130.6 (C), 144.3 (C), 151.4 (C).
(d, JZ8.4 Hz, 1H), 7.05 (m, 2H), 7.72 (d, JZ15.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) d: K4.2 (CH3–Si), 18.9 (C),
26.0 (CH3), 55.8 (OCH3), 111.4 (CH), 115.3 (CH), 121.5
(CH), 123.1 (CH), 128.3 (C), 147.6 (C), 148.4 (CH), 151.6
(C), 173.0 (C]O).
4.5.2. 4-O-t-Butyldimethylsilylcoumaric acid 1b. Accord-
ing to the general procedure from 8b: isolated yield 88%20;
1H NMR (300 MHz, CDCl3) d: 0.22 (s, 6H), 0.99 (s, 9H),
6.29 (d, JZ15.8 Hz, 1H), 6.86 (d, JZ8.4 Hz, 2H), 7.45 (d,
JZ8.4 Hz, 2H), 7.74 (d, JZ15.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) d: K4.0 (CH3–Si), 18.6 (C), 26.0
(CH3), 115.1 (CH), 120.9 (CH), 127.7 (C), 130.4 (CH),
147.1 (CH), 158.6 (C), 172.8 (C]O).
4.3.2. 1-Bromo-2-hydroxy-3-(3,4-di-t-butyldimethylsilyl-
oxy)phenyl propane 6b. According to the general pro-
cedure from 5b: 60% isolated yield; H NMR (300 MHz,
CDCl3) d 0.21 (s, 12H), 1.00 (s, 18H), 2.80 (t, JZ6 Hz, 2H),
3.38 (dd, JZ10.5 Hz, JZ6 Hz, 1H), 3.49 (dd, JZ10.5 Hz,
JZ4.1 Hz, 1H), 3.96 (m, 1H), 6.70 (m, 3H); 13C NMR
(75 MHz, CDCl3) d: K3.7 (CH3–Si), 18.8 (C), 26.3 (CH3),
39.4 (CH2), 41.1 (CH2), 72.2 (CH), 121.5 (CH), 122.5 (CH),
130.1 (C), 146.2 (C), 147.2 (C).
1
4.6. Coupling reaction
4.4. Dess–Martin oxidation13
The acid was dissolved in an aqueous solution of NaOH
(0.19 M, 1.2 equiv) and added to a solution of bromoketone
in toluene (1 equiv, 0.16 M) and NBu4Br (0.5 equiv). The
reaction mixture was stirred at room temperature for
12–24 h. After extraction with toluene–water, the organic
phase was dried with MgSO4, concentrated and purified by
flash column chromatography on silica gel (petroleum
ether/ethyl acetate 8:2).
To a solution of alcohol (1 equiv) in CH2Cl2 (0.2 M) was
added 1.1 equiv of the commercial Dess–Martin reagent in
CH2Cl2 (15%). The reaction mixture was stirred at room
temperature under argon for 15 h. Then, Et2O and NaOH
(1.3 M) were added and the organic phase was washed with
water, dried other MgSO4, filtered and concentrated. After
flash column chromatography on silica gel (petroleum
ether/ethyl acetate 85:15) the pure ketone was obtained.
4.6.1. Synthesis of 9a. According to the general procedure
from 1a and 3b: isolated yield 57%; oil; 1H NMR
(300 MHz, CDCl3) d: 0.18 (s, 12H), 0.2 (s, 6H), 1.00 (s,
27H), 3.64 (s, 2H), 3.84 (s, 3H), 4.68 (s, 2H), 6.38 (d, JZ
15.8 Hz, 1H), 6.67–7.03 (m, 6H), 7.66 (d, JZ15.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) d: K4.2 and K3.7 (CH3–Si),
18.8 (C), 26.01 and 26.03 (CH3), 46.7 (CH2), 55.8 (OCH3),
67.7 (CH2), 111.3 (CH), 115.5 (CH), 121.5 (CH), 121.6
(CH), 122.4 (CH), 122.7 (CH), 123.1 (CH), 126.3 (C), 128.4
(C), 146.8 (CH), 147.7 (C), 148.2 (C), 151.6 (C),
169.7(C]O), 202.5(C]O).
4.4.1. 1-Bromo-2-keto-3-(3-methoxy-4-t-butyldimethyl-
silyloxy)phenyl propane 3a. According to the general
procedure from 6a: 78% isolated yield; 1H NMR (300 MHz,
CDCl3) d: 0.16 (s, 6H), 1.00 (s, 9H), 3.80 (s, 3H), 3.83 (s,
2H), 3.91 (s, 2H) 6.75 (m, 3H); 13C NMR (75 MHz, CDCl3)
d: K4.2 (CH3–Si), 18.8 (C), 26.0 (CH3), 47.1 (CH2), 47.9
(CH2), 55.9 (CH3), 113.5 (CH), 121.5 (CH), 122.2 (CH),
126.4 (C), 144.9 (C), 151.6 (C), 200.5 (C]O).
4.4.2. 1-Bromo-2-keto-3-(3,4-di-t-butyldimethylsilyl-
oxy)phenyl propane 3b. According to the general
procedure from 6b: 70% isolated yield; 1H NMR
(300 MHz, CDCl3) d: 0.21 (s, 12H), 1.00 (s, 18H), 3.81 (s,
2H), 3.90 (s, 2H), 6.71 (m, 3H); 13C NMR (75 MHz, CDCl3)
d: K3.7 (CH3–Si), 18.8 (C), 26.3 (CH3), 33.6 (CH2), 46.6
(CH2), 121.7 (CH), 122.6 (CH), 122.7 (CH), 126.4 (C),
146.8 (C), 147.5 (C); 200.0 (C]O).
4.6.2. Synthesis of 9b. According to the general procedure
from 1a and 3a: isolated yield 51%; oil; 1H NMR
(300 MHz, CDCl3) d 0.16 (s, 6H), 0.19 (s, 6H), 1.00 (s,
9H), 1.01 (s, 9H), 3.71 (s, 2H), 3.81 (s, 3H), 3.85 (s, 3H),
4.82 (s, 2H), 6.39 (d, JZ15.8 Hz, 1H), 6.69–7.26 (m, 6H),
7.70 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
K4.23 and K4.19 (CH3–Si), 18.8 (C), 26.04 and 26.10
(CH3), 46.7 (CH2), 55.8 (OCH3), 67.7 (CH2), 111.3 (CH),
113.5 (CH), 114.8 (CH), 121.5 (CH), 122.2 (CH), 122.9
(CH), 126.5 (C), 128.4 (C), 144.8 (C), 146.7 (CH), 148.2
(C), 151.6 (C), 166.7 (C]O), 202.5 (C]O).
4.5. Saponification of the silylester19
To a solution of silyl ester in THF (4.5 mL/mmol)/MeOH
(12.7 mL/mmol) was added drop wise at room temperature,
0.003 equiv of an aqueous solution of K2CO3 (0.7 mmol/L).
After 30 min, the organic solvents were evaporated. Et2O
and saturated solution of NaCl were added. At 0 8C, the
aqueous phase was acidified with HCl 10% to pH 6 and
extracted with Et2O. After drying of the organic phase with
MgSO4, filtration and evaporation of ether, the product was
recovered quantitatively and used in the following step
without further purification.
4.6.3. Synthesis of 9c. According to the general procedure
from 1b and 3a: isolated yield 62%; oil; 1H NMR
(300 MHz, CDCl3) d: 0.15 (s, 6H), 0.22 (s, 6H), 0.99 (s,
18H), 3.70 (s, 2H), 3.78 (s, 3H), 4.80 (s, 2H), 6.37 (d, JZ
15.9 Hz, 1H), 6.7–6.85 (m, 5H), 7.43 (d, JZ8.5 Hz, 1H),
7.69 (d, JZ15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
K4.2 and K4.0 (CH3–Si), 18.6 and 18.8 (C), 26.0 and 26.1
(CH3), 46.6 (CH2), 55.8 (OCH3), 67.8 (CH2), 113.5 (CH),
114.8 (CH), 120.9 (CH), 121.5 (CH), 122.2 (CH), 126.5 (C),
130.3 (CH), 144.8 (C), 146.3 (C), 151.5 (C), 158.5 (C),
166.7 (C]O), 202.5 (C]O).
4.5.1. 3-Methoxy-4-t-butyldimethylsilyloxy-cinnamic
acid 1a. According to the general procedure from 8a:
isolated yield 90%; 1H NMR (300 MHz, CDCl3) d: 0.18 (s,
6H), 1.0 (s, 9H), 3.84 (s, 3H), 6.31 (d, JZ15.8 Hz, 1H), 6.86
4.6.4. Synthesis of 9d. According to the general procedure

F. Fache et al. / Tetrahedron 61 (2005) 5261–5266
5265
1
from 1c and 3a: isolated yield 41%; oil; 1H NMR
(300 MHz, CDCl3) d: 0.16 (s, 6H), 1.01 (s, 9H), 3.72 (s,
2H), 3.81 (s, 3H), 3.93 (s, 6H), 4.83 (s, 2H), 6.40 (d, JZ
15.5 Hz, 1H), 6.69–7.18 (m, 6H), 7.70 (d, JZ15.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) d: K4.2 (CH3–Si), 18.8 (C),
26.1 (CH3), 46.7 (CH2), 55.9, 56.3 and 56.4 (OCH3), 67.7
(CH2), 110.0, 111.4, 114.8, 121.5, 122.2 and 123.3 (CH),
126.5 (C), 127.5 (C), 146.5 (CH), 151.6 (C), 151.8 (C]O),
202.4 (C]O).
from 9b: isolated yield 32%; mpZ113–115 8C; H NMR
(300 MHz, CDCl3) d: 3.66 (s, 2H), 3.81 (s, 3H), 3.85 (s, 3H),
4.80 (s, 2H), 6.32 (d, JZ15.8 Hz, 1H), 6.67–7.03 (m, 6H),
7.63 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
46.3 (CH2), 56.1 (OCH3), 67.7 (CH2), 109.8, 112.1, 114.1,
115.0, 115.1, 122.5, 123.6, 124.7 (CH), 126.8 and 145.2 (C),
146.6 (CH), 147.1 and 148.6 (C), 166.7 (C]O), 202.5
(C]O); CI-LRMS m/z 373 (MCHC%), 372 (MC%), 195,
177; CI-HRMS calcd for C20H21O7 (MCHC%) 373.1287,
found 373.1288.
4.6.5. Synthesis of 9e. According to the general procedure
from 1c and 3b: this product turned out to be very unstable
and therefore was immediately engaged in the following
step without purification to give 10e after deprotection.
4.7.3. Synthesis of 10c. According to the general procedure
from 9c: isolated yield 26%; mpZ99–100 8C; H NMR
1
(300 MHz, CDCl3CCD3OD) d: 3.64 (s, 2H), 3.78 (s, 3H),
4.75 (s, 2H), 6.27 (d, JZ15.8 Hz, 1H), 6.63–6.78 (m, 5H),
7.34 (d, JZ8.5 Hz, 1H), 7.64 (d, JZ15.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3CCD3OD) d: 46.2 (CH2), 56.0
(OCH3), 67.6 (CH2), 112.3, 113.2, 115.2, 116.1, 122.4 and
124.5 (CH), 126.0, 130.4 and 145.3 (C), 146.8 (CH), 147.4
and 159.7 (C), 167.1 (C]O), 203.1 (C]O); EI-LRMS m/z
342 (MC%), 205, 147, 137; EI-HRMS calcd for C19H18O6
(MC%) 342.1103, found 342.1105.
4.6.6. Synthesis of 9f. According to the general procedure
from 1b and 3b: isolated yield 66%; oil; 1H NMR
(300 MHz, CDCl3) d: 0.17 (s, 6H), 0.18 (s, 6H), 0.2 (s,
6H), 0.97 (s, 27H), 3.63 (s, 2H), 4.76 (s, 2H), 6.36 (d, JZ
15.8 Hz, 1H), 6.63–6.89 (m, 5H), 7.41 (d, JZ8.4 Hz, 2H),
7.68 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
K3.9 and K3.7 (CH3–Si), 18.6 and 18.8 (C), 26.0 and 26.3
(CH3), 46.4 (CH2), 67.7 (CH2), 114.8 (CH), 120.9 (CH),
121.7 (CH), 122.7 (CH), 126.2 (C), 127.9 (C), 130.2 (CH),
146.3 (CH), 146.7 (C), 147.4 (C), 166.7 (C), 175.7 (C),
202.4 (C]O).
4.7.4. Synthesis of 10d. According to the general procedure
from 9d: isolated yield 45% (oil); 1H NMR (300 MHz,
CDCl3) d: 3.71 (s, 2H), 3.86 (s, 3H),3.91 (s, 6H), 4.84 (s,
2H), 6.40 (d, JZ15.8 Hz, 1H), 6.72–6.88 (m, 4H), 7.10 (m,
2H), 7.7 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz, CDCl3C
CD3OD) d: 46.24 (CH2), 56.3 (CH3), 67.8 (CH2), 110.1,
111.4, 112.2, 114.7, 115.1, 122.7 and 123.4 (CH), 124.9,
127.5 and 145.4 (C), 146.6 (CH), 147.2, 149.6 and 151.8
(C), 166.7 (C]O), 202.6 (C]O); EI-LRMS m/z 386 (MC%),
249, 208, 191(100), 163, 137; EI-HRMS calcd for C21H22O7
(MC%) 386.1365, found 386.1369.
4.6.7. Synthesis of 9g. According to the general procedure
from 1d and 3a: isolated yield 70%; oil; 1H NMR
(300 MHz, CDCl3) d: 0.15 (s, 6H), 1.00 (s, 9H), 3.71 (s,
2H), 3.79 (s, 3H), 4.82 (s, 2H), 6.52 (d, JZ15.8 Hz, 1H),
6.68 (m, 2H), 6.85 (d, JZ8.4 Hz, 1H), 7.39 (m, 3H), 7.53
(m, 2H), 7.76 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d: K4.2 (CH3–Si), 18.8 (C), 26.1 (CH3), 46.7
(CH2), 55.9 (OCH3), 67.8 (CH2), 113.5, 117.2, 121.5, 122.2
and 128.6 (CH), 129.3 (C), 131.0 (CH), 146.6 (CH), 150.0
(C), 151.6 (C), 166.4 (C]O), 202.3 (C]O).
4.7.5. Synthesis of 10e. According to the general procedure
from 9e (see above): isolated yield 12% in two steps; H
1
NMR (300 MHz, CDCl3CCD3OD) d: 3.40 (s, 2H), 3.66 (s,
6H), 4.59 (s, 2H), 6.14 (d, JZ15.8 Hz, 1H), 6.33–6.91 (m,
6H), 7.46 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3CCD3OD) d: 46.2 (CH2), 57.6 (OCH3), 62.3
(CH2), 111.6, 112.8, 115.8, 117.2, 118.0, 122.6 (CH),
124.7, 125.9, 128.8, 145.8 and 146.7 (C),148.0 (CH), 150.8
(C]O), 204.9 (C]O); CI-LRMS m/z 373 (MCHC%), 355,
209 (100), 191, 165; CI-HRMS calcd for C20H21O7 (MC
4.7. Deprotection of the silyl ethers20
To a diluted solution of silyl ether in acetonitrile (0.2 M)
was added carefully aqueous HF (48–51%) (two volumes of
CH3CN for one volume HFaq). The solution was stirred at
room temperature for 30 min and then aqueous NaOH (8%)
was added. The organic phase was extracted with CH2Cl2,
dried over MgSO4, concentrated and the crude product was
purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate 1:1).
H
C%) 373.1287, found 373.1285.
4.7.6. Synthesis of 10f. According to the general procedure
1
from 9f: isolated yield 30%; mpZ172–177 8C; H NMR
4.7.1. Synthesis of cimiracemate B 10a.6 According to the
general procedure from 9a: isolated yield 10%; H NMR
(300 MHz, CDCl3CCD3OD) d: 3.59 (s, 2H), 3.78 (s, 3H),
4.76 (s, 2H), 6.28 (d, JZ15.8 Hz, 1H), 6.53–6.80 (m, 5H),
7.36 (m, 2H), 7.62 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3CCD3OD) d: 46.0 (CH2), 67.5 (CH2), 113.1, 115.6,
115.9, 116.3 and 121.2 (CH), 124.5 and 125.8 (C), 130.3
(CH), 144.2 and 145.0(C), 146.7 (CH), 159.8 (C), 167.2
(C]O), 203.4 (C]O); CI-LRMS m/z 329 (MCHC%), 183,
1
(300 MHz, CD3OD) d: 3.69 (s, 2H), 3.90 (s, 3H), 4.87 (s,
2H), 6.43 (d, JZ15.8 Hz, 1H), 6.60–6.84 (m, 4H), 7.08–
7.21 (m, 2H), 7.66 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz,
CD3OD) d: 46.6 (CH2), 56.7 (CH3), 68.8 (CH2), 112.1,
114.8, 116.2, 116.8, 117.9, 122.3 and 124.3 (CH), 124.6,
126.3, 127.9, 128.1 and 145.9 (C), 146.8 (CH), 147.2, 148.0,
149.7and 151.1 (C), 168.6 (C]O), 204.9 (C]O); CI-
LRMS m/z 359 (MCHC%), 313, 235, 217, 195 (100), 177,
167; CI-HRMS calcd for C19H19O7 (MCHC%) 359.1131,
found 359.1133.
165, 147; CI-HRMS calcd for C18H17O6 (MCHC%
)
329.1025, found 329.1025.
4.7.7. Synthesis of 10g. According to the general procedure
from 9g: isolated yield 44%; PF 1H NMR (300 MHz,
CDCl3) d 3.64 (s, 2H), 3.88 (s, 3H), 4.83 (s, 2H), 6.52 (d, JZ
15.9 Hz, 1H), 6.74 (m, 2H), 6.87 (m, 1H), 7.41 (m, 3H), 7.53
4.7.2. Synthesis of 10b. According to the general procedure

5266
F. Fache et al. / Tetrahedron 61 (2005) 5261–5266
(m, 2H), 7.76 (d, JZ15.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 46.5 (CH2), 56.3 (OCH3), 67.9 (CH2), 112.1,
113.7, 115.1, 117.1, 122.7 (CH), 124.9 (C), 128.6, 129.3 and
131.0 (CH), 134.5 and 145.4 (C), 146.7 (CH), 147.2, 166.5
(C]O), 202.4 (C]O); EI-LRMS m/z 326 (MC%), EI-
HRMS calcd for C19H18O5 (MC%) 326.1154, found
326.1161.
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Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem.
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