Chemoenzymatic total synthesis of a naturally occurring (5-5′)/(8′-O-4-″) dehydrotrimer of ferulic acid

Article abstract of DOI:10.1002/ejoc.201201290

The cross-linking of plant cell walls by ferulate dehydrodimerization reactions is well established. Recently, a (5-5′)/(8′-O-4-″) dehydrotrimer of ferulic acid (A) was isolated from alkali extracts of maize bran. Its structure was elucidated on the basis of an extensive structural analysis (UV, MS, 1D and 2D NMR). This first identified ferulic acid dehydrotrimer has revealed that parietal polysaccharide chains can be more extensively cross-linked than has been previously recognized. To produce the (5-5′)/(8′-O-4-″) dehydrotrimer (A) in sufficient high-purity quantities and allow the development of analytical methodologies (e.g., LC/GC, immunohistochemistry) to identify and quantify this peculiar trimer in plant extracts or samples, its first total convergent synthesis has been achieved in 10 steps and in 18 % yield starting from commercially available vanillin by horseradish peroxidase mediated enzymatic aryl-aryl coupling, aldolization/crotonization, and Wittig olefination reactions as the key steps. The first total convergent synthesis of the naturally occurring (5-5′)/(8′-O-4-″) dehydrotrimer of ferulic acid (A) has been achieved in 10 steps and in 18 % yield starting from commercially available vanillin using horseradish peroxidase mediated enzymatic aryl-aryl coupling, aldolization/crotonization, and Wittig olefination reactions as the key steps. Copyright

Full text of DOI:10.1002/ejoc.201201290

FULL PAPER
DOI: 10.1002/ejoc.201201290
Chemoenzymatic Total Synthesis of a Naturally Occurring (5-5Ј)/(8Ј-O-4ЈЈ)
Dehydrotrimer of Ferulic Acid
Louis M. M. Mouterde,[a] Amandine L. Flourat,[a] Molly M. M. Cannet,[a]
Paul-Henri Ducrot,[a] and Florent Allais*[a]
Keywords: Natural products / Total synthesis / C–C coupling / Enzyme catalysis
The cross-linking of plant cell walls by ferulate dehydrodi- ficient high-purity quantities and allow the development of
merization reactions is well established. Recently, a (5-5Ј)/
(8Ј-O-4ЈЈ) dehydrotrimer of ferulic acid (A) was isolated from
alkali extracts of maize bran. Its structure was elucidated on
the basis of an extensive structural analysis (UV, MS, 1D and
2D NMR). This first identified ferulic acid dehydrotrimer has
revealed that parietal polysaccharide chains can be more ex-
tensively cross-linked than has been previously recognized.
To produce the (5-5Ј)/(8Ј-O-4ЈЈ) dehydrotrimer (A) in suf-
analytical methodologies (e.g., LC/GC, immunohistochem-
istry) to identify and quantify this peculiar trimer in plant ex-
tracts or samples, its first total convergent synthesis has been
achieved in 10 steps and in 18% yield starting from commer-
cially available vanillin by horseradish peroxidase mediated
enzymatic aryl–aryl coupling, aldolization/crotonization, and
Wittig olefination reactions as the key steps.
pling reaction,[12] much like the radical coupling of mono-
lignols in lignins.[13] A range of dehydrodiferulic acids can
be found in a variety of materials,[12,14–18] as predicted and
confirmed in 1994.[12] Dehydrodiferulic acids are charac-
terized by the new bond formed in the coupling between
the two ferulic acids (at their 4-O-, 5-, or 8-positions) as (5-
5Ј), (8-8Ј), (8-5Ј), (8-5Ј benzofuran), (8-O-4Ј), and (4-O-5Ј)
dehydrodimers (Figure 1). More recently, new (5-5Ј)/(8Ј-O-
4ЈЈ) dehydrotrimer A from ferulic acid was identified and
isolated from maize bran extracts.[19,20]
A general issue for the development of analytical meth-
odologies to identify ferulic acid dimers and trimers in com-
plex mixtures resulting from biomass treatment is the avail-
ability of pure standard compounds allowing researchers to
validate the methodologies used. Although efficient synthe-
ses of ferulic acid dimers have been described,[12] none have
been published for trimers. It became crucial to develop
new convenient and straightforward synthetic routes to
these trimers, not only to allow reliable quantification in
plant extracts (e.g., LC/GC standards), but also to develop
specific antibodies for their accurate localization in plant
tissues using immunohistochemistry techniques. In ad-
dition, such compounds and their esters often exhibit po-
tent biological properties and can prove themselves poten-
tial drug candidates.[21]
Introduction
Ferulic acid (1) is one of the most abundant phenolic
acids found in grasses. First isolated in the early 1900s, its
biosynthesis is still obscure and remains under investiga-
tion. Nevertheless, some recent studies tend to prove that
ferulic acid might be obtained from caffeic acid by the ac-
tion of the enzyme O-methyl transferase.[1] Although pres-
ent in seeds as the free acid and low-molecular-weight con-
jugates,[2] ferulic acid is found mostly as an ester-linked sub-
stituent of cell wall heteroxylans, especially in the brans.
The cross-linking of plant cell walls by ferulate dehydrodi-
merization reactions is well established.[1–6] Ferulic acid
acylates various polysaccharides, notably arabinoxylans in
grasses,[3] particularly in the insoluble fiber fraction.[7,8]
Ferulate dehydrodimerization is therefore a mechanism for
linking two polysaccharide chains, providing structural in-
tegrity to the cell wall, but inhibiting fiber degradability.[9]
As phenolic entities are involved in radical coupling reac-
tions, ferulic acid may also be incorporated into lignin poly-
mers as monomer or oligomer,[4,10] furthering the cross-
linking of the cell wall biopolymers and thereby limiting the
degradability of the polysaccharides.[11] The dehydrodimer-
ization reaction is described as a combinatorial radical cou-
Herein we would like to report the first total synthesis of
(5-5Ј)/(8Ј-O-4ЈЈ) dehydrotrimer A starting from commer-
cially available vanillin (2) by a convergent synthetic path-
way in which the aryl–aryl bond (5-5Ј), the two α,β-unsatu-
rated carboxylic acids, and the internal α-phenoxy α,β-un-
saturated carboxylic acid were formed by horseradish per-
oxidase (HRP) mediated enzymatic oxidative coupling, two
[a] INRA/AgroParisTech, UMR1318 Institut Jean-Pierre Bourgin,
RD10, 78026 Versailles Cedex, France
Fax: +33-1-30833119
E-mail: florent.allais@versailles.inra.fr
Homepage: http://www-ijpb.versailles.inra.fr/en/pave/equipes/
lignines-tanins/index.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201290.
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Figure 1. Naturally occuring dehydrodimers and -trimer of ferulic acid.
Scheme 1. Retrosynthetic strategy for the synthesis of (5-5Ј)/(8Ј-O-4ЈЈ) dehydrotrimer A.
Wittig olefination reactions, and a condensation reaction, tig olefination at 0 °C. In fact, dropwise addition of strictly
respectively (Scheme 1).
1 equiv. of (tert-butoxycarbonylmethylene)triphenylphos-
phorane (Ph3P=CHCO2tBu) to a diluted solution of 5 in
dichloromethane provided the desired mono-α,β-unsatu-
rated ester 3 in 60% yield (50% overall yield from 2, three
Results and Discussion
Our efforts were first focused on the synthesis of the pro- steps, E/Z ratio[23] 95:5) along with the corresponding bis-
tected biaryl intermediate 3 featuring the 5-5Ј interunit α,β-unsaturated ester 3-bis (18%) and unreacted dialdehyde
bonding pattern (Scheme 2). Oxidative C–C coupling of va- 5 (4%). The tert-butyl esters were chosen because of their
nillin (2) in the presence of HRP and hydrogen peroxide selective, mild, and easy removal with trifluoroacetic acid
at pH 4.2 in a buffered citrate/phosphate aqueous solution (TFA) even in the presence of phenolic acetates.
afforded bis-vanillin 4 in excellent yield (97%).[22] The free
The tert-butyl α-phenoxy acetate 6 was synthesized start-
phenols were then acylated by using acetic anhydride in ing from the deprotonation of vanillin (2; K2CO3, anhy-
pyridine to give the symmetrical dialdehyde 5 in 86% yield. drous DMF), directly followed by the addition of tert-butyl
At this stage, a desymmetrization process had to be per- bromoacetate (BrCH2CO2tBu) to provide key intermediate
formed to selectively functionalize only one of the two alde- 7 in 95% yield. Subsequent protection of aldehyde 7 with
hydes. This was successfully achieved through a classic Wit- methyl orthoformate in the presence of a catalytic amount
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Total Synthesis of a Dehydrotrimer of Ferulic Acid
Scheme 2. Synthesis of protected 5-5Ј biaryl moiety 3 and key intermediate 6.
of pTsOH afforded dimethyl acetal 6 in 99% yield (94%, corresponding aldehyde in quantitative yield. Subsequent
two steps; Scheme 2).[24] With both key intermediates 3 and Wittig olefination with (tert-butoxycarbonylmethylene)tri-
6 in hand, we were able to proceed to the creation of the phenylphosphorane in 1,2-dimethoxyethane (1,2-DME)[28]
remaining 8Ј-O-4ЈЈ interunit bond by the formation of β- at reflux afforded compound 10 in 88% yield and with a
hydroxy ester 8.
97:3 E/Z ratio.[23] At this stage, two options were offered to
As depicted in Scheme 3, tert-butyl α-phenoxy acetate 6 achieve desired trimer A: Both acetates and tert-butyl esters
was deprotonated with lithium diisopropylamide (LDA) in could be removed simultaneously by a classic saponification
freshly distilled THF at –78 °C and the corresponding ester reaction, or the tert-butyl esters or acetates could be selec-
enolate was subsequently treated with aldehyde 3 to give tively deprotected for subsequent regioselective functionali-
aldol
8 in 80% yield as an erythro/threo mixture zation. To demonstrate this concept, we chose a two-step
(3:2).[23,25,26] β-Hydroxy ester 8 was then immediately mesy- deprotection process for the clean and mild sequential re-
lated (MsCl, TEA) and transformed, through DBU-medi- moval of the acetate and tert-butyl protecting groups. In
ated dehydration, to the desired Z-unsaturated ester 9 (77% this manner, treatment of 10 with NaOMe in MeOH pro-
yield, 58% overall yield from 6, 95:5 Z/E ratio).[27] Selective vided bis-phenol 11 in 71% yield. The tert-butyl esters were
acid-mediated deprotection of the dimethyl acetal moiety then efficiently cleaved in the presence of TFA to afford (5-
by treatment of a solution of 9 in ethyl acetate with a satu- 5Ј)/(8Ј-O-4ЈЈ) dehydrotrimer A in 99% yield (18% overall
rated aqueous ammonium chloride solution provided the yield, 10 steps from vanillin). The analytical and spectro-
Scheme 3. Aldolization, crotonization, and the final steps of the synthesis of (5-5Ј)/(8Ј-O-4ЈЈ)-dehydrotrimer A.
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36.5 °C overnight. The precipitate was filtered and washed with
water and then chloroform to give the dialdehyde 4 (4.4 g, 97%).
scopic data of A are in good agreement with those reported
in the literature.[19a] Note, this sequence can also be inverted
if one wants to saponify the tert-butyl esters first.
Iron(III)-Mediated Procedure:[22c] FeSO4 (0.4 g, 1.4 mmol) was
added to vanillin (2; 10.64 g, 70 mmol) in water (700 mL) whilst
stirring. After heating for 10 min at 50 °C, Na2S2O8 (8.93 g,
37.5 mmol) was added and the reaction mixture was stirred at
50 °C for 5 d. The brown precipitate formed was removed by fil-
tration. The solid was then dissolved in NaOH (2 m) solution. HCl
(2 m) was added to precipitate dialdehyde 4, which was isolated
Conclusions
The first total convergent synthesis of the naturally oc-
curring (5-5Ј)/(8Ј-O-4ЈЈ) dehydrotrimer of ferulic acid (A)
has been successfully achieved in 10 steps and in 18% over-
all yield starting from commercially available vanillin by
HRP-mediated enzymatic aryl–aryl coupling, aldol-like
condensation/crotonization, Wittig olefination reactions,
and desymmetrization as the key steps. The use of orthogo-
nal protecting groups such as tert-butyl esters and acetates
offers great flexibility and demonstrates the high potential
of this synthetic route in terms of the scope of the targets
(e.g., polyacids, polyols, polyesters) and their applications
by filtration (10.0 g, 95%), m.p. 315–316 °C. IR (neat): ν = 3250,
˜
1
1671 cm–1. H NMR ([D6]DMSO, 300 MHz): δ = 9.81 (s, 2 H, 7-
H, 2 CHO), 7.43 (s, 4 H, 2-H, 6-H), 3.93 (s, 6 H, 8-H, OCH3) ppm.
13C NMR ([D6]DMSO, 75 MHz): δ = 191.0 (d, C-7, 2 CHO), 150.9
(s, C-4), 148.3 (s, C-3), 128.1 (d, C-1), 127.6 (s, C-6), 124.7 (s, C-
5), 109.1 (d, C-2), 56.0 (s, C-8, OCH3) ppm. MS (EI, 50 eV): m/z
(%) = 301 (100) [M – H]+, 151 (5). HRMS (EI): calcd. for C16H13O6
[M – H]+ 301.0712; found 301.0716.
5,5Ј-Diformyl-3,3Ј-dimethoxy-[1,1Ј-biphenyl]-2,2Ј-diyl Diacetate (5):
A solution of 4 (2.00 g, 6.62 mmol) in acetic anhydride (4.73 g,
(e.g., chromatographic samples, antibodies, bioactive com- 4.38 mL, 46.31 mmol) and pyridine (2 mL) was stirred at room
temperature for 6 h. The mixture was then poured into an ice/water
mixture (30 mL), which was stirred for 1 h. The solid was then fil-
tered and dried to provide pure 5 (2.2 g, 86%), m.p. 125–130 °C.
pounds). As part of a collaborative research project aiming
at the localization and quantification of this trimer in grass
tissues (e.g., wheat, maize and miscanthus) by immuno-
histochemistry, we are currently applying this synthesis to
the production of specific antibodies. This work will be re-
ported in due course.
IR (neat): ν = 1770, 1695, 1196 cm–1. 1H NMR (300 MHz, CDCl ):
˜
3
δ = 9.98 (s, 2 H, 7-H, 2 CHO), 7.63 (s, 2 H, 6-H), 7.46 (s, 2 H, 2-
H), 3.94 (s, 6 H, 8-H, 2 OCH3), 2.05 (s, 6 H, 10-H, 2 Ac) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 190.7 (d, C-7, CHO), 167.8 (s, C-9),
152.5 (s, C-3), 142.9 (s, C-4), 134.8 (s, C-1), 131.4 (s, C-5), 126.5
(d, C-6), 110.5 (d, C-2), 56.4 (q, C-8), 20.4 (q, C-10) ppm. MS (EI+,
50 eV): m/z (%) = 404 (100) [M + NH4]+, 401 (62), 387 (42), 359
(16), 345 (5), 295 (9). HRMS (EI): calcd. for C20H19O8 [M + H]+
301.1080; found 387.1085.
Experimental Section
General: CH2Cl2 (stabilized with amylene) was purified by distil-
lation from CaH2 under N2 immediately before use. THF and Et2O
were purified by distillation from sodium/benzoquinone under N2.
Moisture- and O2-sensitive reactions were carried out in flame-
dried glassware under Ar. Evaporations were conducted under re-
duced pressure at temperatures below 35 °C unless otherwise noted.
Column chromatography (CC) was carried out with an automated
flash chromatography PuriFlash system and pre-packed
INTERCHIM PF-30SI-HP (30 μm silica gel) columns. 1H NMR
spectra of samples in the indicated solvent were recorded at
300 MHz at 20 °C [1H NMR: CDCl3 residual signal at δ =
7.26 ppm, [D6]DMSO residual signal at δ = 2.50 ppm, and (CD3)2-
CO residual signal at δ = 2.05 ppm]. 13C NMR spectra of samples
in the indicated solvent were recorded at 75 MHz at 20 °C [13C
NMR: CDCl3 residual signal at δ = 77.16 ppm, [D6]DMSO resid-
ual signal at δ = 39.5 ppm, and (CD3)2CO residual signal at δ =
29.84 ppm]. The atomic labeling used in the assignment of NMR
signals is presented in the Supporting Information. All reported
yields are uncorrected and refer to purified products. Low- and
high-resolution mass spectra (HRMS) were obtained by the Small
Molecule Mass Spectrometry platform of IMAGIF (CNRS-Gif-
sur-Yvette, France). All reagents were purchased from Sigma–Ald-
rich and used without further purification.
(E)-5-[3-(tert-Butoxy)-3-oxoprop-1-en-1-yl]-5Ј-formyl-3,3Ј-dimeth-
oxy-[1,1Ј-biphenyl]-2,2Ј-diyl Diacetate (3):
(tert-butoxycarbonylmethylene)triphenylphosphorane
A
solution of
(487 mg,
1.29 mmol) in DCM (26 mL) was added dropwise to a solution of
5 (500 mg, 1.29 mmol) in freshly distilled DCM (26 mL) at 0 °C
over a 1 h period through a syringe pump. The mixture was
quenched with H2O (30 mL) and the aqueous layer was extracted
with AcOEt (3ϫ30 mL). The combined organic extracts were dried
with anhydrous MgSO4, filtered, and concentrated in vacuo. The
crude product was then purified by flash chromatography (cyclo-
hexane/AcOEt, 8:2) to give pure compound 3 (95:5 E/Z ratio) as a
white solid (376 mg, 60%). The pure corresponding diester 3-bis
was also recovered in 18% yield. Important note: To scale up the
reaction to “nϫ1.29” mmol of 5, one must add the phosphorane
solution over a period of “n” hours.
Major Product 3: M.p. 87–89 °C. IR (neat): ν = 1769, 1698,
˜
1189 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.94 (s, 1 H, 7Ј-H,
CHO), 7.54 (d, J = 15.9 Hz, 1 H, 8-H), 7.53 (s, 1 H, 6Ј-H), 7.38 (s,
1 H, 6-H), 7.14 (s, 1 H, 2Ј-H), 7.02 (s, 1 H, 2-H), 6.32 (d, J =
15.9 Hz, 1 H, 7-H), 3.93 (s, 3 H, 10-H or 10Ј-H), 3.89 (s, 3 H, 10Ј-
H or 10-H), 2.13 (s, 3 H, 12-H or 12Ј-H), 2.10 (s, 3 H, 12Ј-H or
12-H), 1.53 (s, 9 H, 14-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
190.7 (d, C-7Ј, CHO), 168.1 (s, C-11 or C-11Ј), 167.7 (s, C-11Ј or
C-11), 165.8 (s, C-9), 152.3 (s, C-3Ј), 151.7 (s, C-3), 142.3 (s, C-4,
C-4Ј), 134.6 (s, C-1Ј), 133.2 (s, C-5Ј), 131.9 (s, C-5), 130.9 (s, C-1),
126.6 (d, C-7), 122.6 (d, C-6, C-6Ј), 121.0 (d, C-8), 110.9 (d, C-2
or C-2Ј), 110.0 (d, C-2Ј or C-2), 80.6 [s, C-13, C(CH3)3], 56.3 (q,
C-10 or C-10Ј, OCH3), 56.1 (q, C-10Ј or C-10, OCH3), 28.1 [q, C-
14, C(CH3)], 20.3 (q, C-12, C-12Ј) ppm. MS (EI+, 50 eV): m/z (%)
= 507 (40) [M + Na]+, 502 (100) [M + NH4]+, 499 (2), 249 (7).
Synthesis of 6,6Ј-Dihydroxy-5,5Ј-dimethoxy-[1,1Ј-biphenyl]-3,3Ј-di-
carbaldehyde (4)
HRP-Mediated Procedure:[22b] Vanillin (2; 5.0 g, 33 mmol) was dis-
solved at 36.5 °C in a minimum volume of citrate/phosphate buffer
(pH 4.2, ca. 500 mL). Horseradish peroxidase (2025 units) was then
poured into the clear solution and the mixture was stirred for an
extra 2 min. Hydrogen peroxide (35% w/v, 2.8 mL) was then added
dropwise over a 5 min period and the reaction was stirred at
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Total Synthesis of a Dehydrotrimer of Ferulic Acid
HRMS (EI): calcd. for C26H28O9Na [M + Na]+ 507.1631; found
507.1646.
tion mixture had turned yellow, the temperature was gradually co-
oled to –78 °C.
1
A solution of 6 (1.03 g, 2.13 mmol) in anhydrous THF (5.7 mL)
was added dropwise to a solution of LDA (3.19 mmol) prepared in
situ at –78 °C over a 20 min period through a syringe pump. The
mixture was stirred for 1 h at this temperature and a solution of 3
(664 mg, 2.13 mmol) in anhydrous THF (5.7 mL) was then added
dropwise over a 20 min period through a syringe pump. The mix-
ture was stirred for 2 h at –78 °C, quenched with H2O (10 mL), and
then the aqueous layer was extracted with AcOEt (3ϫ10 mL). The
combined organic extracts were dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The crude product was then puri-
fied by flash chromatography. Starting with 8:2 cyclohexane/AcOEt
as eluent, unreacted 3 and 6 were obtained, and then changing
the eluent to 5:5 cyclohexane/AcOEt afforded compound 8 (3:2
Minor Product 3-bis: H NMR (300 MHz, CDCl3): δ = 7.56 (d, J
= 15.6 Hz, 1 H, 8-H), 7.14 (s, 1 H, 6-H), 7.03 (s, 1 H, 2-H), 6.35
(d, J = 15.9 Hz, 1 H, 7-H), 3.91 (s, 6 H, 10-H), 2.13 (s, 6 H, 12-
H), 1.55 (s, 18 H, 14-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
168.3 (s, C-11), 166.1 (s, C-9), 151.7 (s, C-3), 142.6 (s, C-4), 139.1
(s, C-1), 133.1 (s, C-5), 131.5 (s, C-7), 122.9 (d, C-6), 120.9 (d, C-
8), 110.7 (d, C-2), 80.7 [s, C-13, C(CH3)3], 56.2 (q, C-10, OCH3),
28.3 [q, C-14, C(CH3)], 20.3 (q, C-12) ppm.
tert-Butyl 2-(4-Formyl-2-methoxyphenoxy)acetate (7): Anhydrous
K2CO3 (13.6 g, 98.4 mmol) was added to a solution of vanillin (2;
10.0 g, 65.6 mmol) in anhydrous DMF (133 mL) and the mixture
was stirred at room temperature for 30 min. The mixture was then
cooled to 0 °C and tert-butyl bromoacetate (14.5 mL, 98.4 mmol)
was added dropwise. The ice bath was then removed and the reac-
tion was stirred at room temperature overnight. The mixture was
then quenched with H2O (200 mL) and the aqueous layer extracted
with AcOEt (3ϫ200 mL). The combined organic extracts were
dried with anhydrous MgSO4, filtered, and concentrated in vacuo.
The crude product was dissolved in a minimum volume of dichloro-
methane, reprecipitated in hexanes, and then filtered to give pure
erythro/threo mixture) as a white solid (1.35 g, 80 %), m.p. 85–
1
90 °C. IR (neat): ν = 1767, 1706, 1591, 1270, 1193 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 7.50 (d, J = 16.2 Hz, 1 H, 7-H), 7.26 (s, 1
H, 6-H), 7.10 (m, 1 H, 6Ј-H), 7.03–6.86 (m, 5 H, 2-H, 2Ј-H, 2ЈЈ-H,
5ЈЈ-H, 6ЈЈ-H), 6.30 (d, J = 15.9 Hz, 1 H, 8-H), 5.32 (s, 1 H, 7ЈЈ-H),
5.18 (m, 0.6 H, 7Ј-H), 5.05 (d, J = 6.0 Hz, 0.4 H, 7Ј-H), 4.68 (d, J
= 3.9 Hz, 0.6 H, 8Ј-H), 4.43 (d, J = 6.6 Hz, 0.4 H, 8Ј-H), 3.87 (s,
9 H, 10-H, 10Ј-H, 10ЈЈ-H), 3.31 (s, 6 H, 8ЈЈ-H), 2.08 (s, 6 H, 12-H,
12Ј-H), 1.53 (s, 9 H, 14-H or 14Ј-H), 1.31 (s, 9 H, 14Ј-H or 14-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.5 (s, C-11 or C-11Ј),
168.3 (s, C-11Ј or C-11), 168.0 (s, C-9Ј), 166.1 (s, C-9), 151.8 (s, C-
3 or C-3Ј), 151.4 (s, C-3Ј or C-3), 151.3 (s, C-3 or C-3Ј), 150.6 (s,
C-4ЈЈ), 150.4 (s, C-4ЈЈ), 147.4 (s, C-3ЈЈ), 147.2 (s, C-3ЈЈ), 142.8 (s,
C-7), 139.3 (s, C-4 or C-4Ј), 137.6 (s, C-5 or C-5Ј), 136.9 (s, C-4Ј
or C-4), 134.0 (s, C-1 or C-1Ј), 133.9 (s, C-1 or C-1Ј), 132.9 (C-5
or C-5Ј), 132.1 (s, C-1Ј or C-1), 131.9 (s, C-1Ј or C-1), 130.9 (s, C-
1ЈЈ), 130.6 (s, C-1ЈЈ), 123.3 (d, C-7), 123.2 (d, C-7), 121.6 (d, C-6
or C-6Ј), 121.2 (d, C-6Ј or C-6), 120.8 (d, C-6ЈЈ), 119.5 (d, C-2ЈЈ),
117.9 (d, C-8), 117.6 (d, C-8), 111.6 (s, C-5ЈЈ), 111.2 (s, C-5ЈЈ), 110.8
(d, C-2 or C-2Ј), 110.7 (d, C-2 or C-2Ј), 110.5 (d, C-2Ј or C-2),
103.1 (d, C-7ЈЈ), 103.0 (d, C-7ЈЈ), 85.1 (d, C-8Ј), 83.4 (d, C-8Ј), 82.7
(s, C-13 or C-13Ј), 80.7 (C-13Ј or C-13), 74.9 (d, C-7Ј), 73.7 (d, C-
7Ј), 56.2 (q, C-10, C-10Ј), 56.0 (q, C-10ЈЈ), 52.8 (q, C-8ЈЈ), 28.3 (q,
C-14, C-14Ј), 27.9 (q, C-14, C-14Ј), 20.5 (q, C-12, C-12Ј) ppm. MS
(EI+, 50 eV): m/z (%) = 819 (100) [M + Na]+, 814 (93), 765 (15).
HRMS (EI): calcd. for C42H52O15Na [M + Na]+ 819.3204; found
819.3218.
compound 7 as a white solid (16.6 g, 95%), m.p. 95–96 °C. IR
(neat): ν = 1743, 1667, 1155 cm–1. H NMR (300 MHz, CDCl ): δ
1
˜
3
= 9.65 (s, 1 H, 7-H, CHO), 7.23 (br. s, 2 H, 2-H, 6-H), 6.69 (d, J
= 8.4 Hz, 1 H, 5-H), 4.51 (s, 2 H, 9-H), 3.73 (s, 3 H, 8-H), 1.29 [s,
9 H, 12-H, C(CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ = 190.9
(d, C-7, CHO), 167.1 (s, C-10, CO2tBu), 152.8 (s, C-4), 150.0 (s, C-
3), 131.0 (s, C-1), 126.2 (d, C-6), 112.2 (d, C-2), 110.0 (d, C-5), 83.0
[s, C-11, C(CH3)3], 66.2 (t, C-9), 56.2 (q, C-8), 28.1 [q, C-12,
C(CH3)3] ppm. MS (EI+, 50 eV): m/z (%) = 330 (40) [M + Na +
CH3CN]+, 308 (14), 289 (23), 284 (34) [M + NH4]+, 267 (20), 252
(12), 211 (10). HRMS (EI): calcd. for C14H19O5 [M + H]+
267.1232; found 267.1241.
tert-Butyl 2-[4-(Dimethoxymethyl)-2-methoxyphenoxy]acetate (6):
Trimethyl orthoformate (13.8 mL, 126 mmol) and p-toluenesulf-
onic acid (36 mg, 0.21 mmol) were added to a solution of 7 (3.0 g,
12.6 mmol) in anhydrous methanol (25 mL) at room temperature.
The mixture was stirred at room temperature for 30 min, quenched
with solid NaHCO3 (100 mg), filtered, and the solid was washed
with AcOEt (50 mL). The combined organic extracts were washed
with brine, dried with anhydrous MgSO4, filtered, and concentrated
in vacuo to give pure compound 6 as an oil (3.55 g, 99%). IR
5-{(Z)-3-(tert-Butoxy)-2-[4-(dimethoxymethyl)-2-methoxyphenoxy]-
3-oxoprop-1-en-1-yl}-5Ј-[(E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]-
3,3Ј-dimethoxy-[1,1Ј-biphenyl]-2,2Ј-diyl Diacetate (9): NEt3
(0.11 mL, 0.76 mmol) and methanesulfonyl chloride (0.06 mL,
0.82 mmol) was added to a solution of 8 (500 mg, 0.63 mmol) in
anhydrous DCM (1.89 mL) at 0 °C. The mixture was stirred over-
night, quenched with a satd. aq. NaHCO3 solution (10 mL), and
the aqueous layer extracted with DCM (3ϫ10 mL). The combined
organic extracts were dried with anhydrous MgSO4 filtered, and
concentrated in vacuo.
(neat): ν = 1754, 1259 cm–1. 1H NMR (300 MHz, CDCl ): δ = 6.83
˜
3
(s, 1 H, 2-H), 6.76 (d, J = 8.1 Hz, 1 H, 6-H), 6.59 (d, J = 8.1 Hz,
1 H, 5-H), 5.15 (s, 1 H, 7-H), 4.41 (s, 2 H, 10-H), 3.72 (s, 3 H, 8-
H), 3.14 (s, 6 H, 9-H), 1.29 [s, 9 H, 13-H, C(CH3)3] ppm. 13C NMR
(75 MHz, CDCl3): δ = 168.0 (s, C-11, CO2tBu), 149.5 (s, C-3),
147.6 (s, C-4), 132.2 (s, C-1), 119.1 (d, C-6), 113.4 (d, C-2), 110.5
(d, C-5), 103.1 (d, C-7), 82.2 [s, C-12, C(CH3)3], 66.7 (t, C-10), 56.0
(q, C-8), 52.7 (q, C-9), 28.1 [q, C-13, C(CH3)3] ppm. MS (EI+,
50 eV): m/z (%) = 335 (49) [M + Na]+, 308 (17), 281 (100), 267
(29), 225 (16), 211 (9). HRMS (EI): calcd. for C16H24O6Na [M +
Na]+ 335.1471; found 335.1473.
The crude mesylate was dissolved in anhydrous THF (1.26 mL)
at room temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU;
0.29 mL, 1.89 mmol) was then added. The mixture was stirred until
TLC indicated complete consumption of the starting material. The
(E)-5-{3-(tert-Butoxy)-2-[4-(dimethoxymethyl)-2-methoxyphenoxy]-
1-hydroxy-3-oxopropyl}-5Ј-[3-(tert-butoxy)-3-oxoprop-1-en-1-yl]- reaction was then quenched with H2O (10 mL) and the aqueous
3,3Ј-dimethoxy-[1,1Ј-biphenyl]-2,2Ј-diyl Diacetate (8): LDA prepa-
ration: A solution of n-butyllithium (2 mL, c = 1.6 m in hexanes,
3.20 mmol) was added dropwise to a solution of redistilled diiso-
propylamine (0.45 mL, 3.20 mmol) in anhydrous THF (3.60 mL) at
0 °C over a 15 min period through a syringe pump. Once the reac-
layer extracted with DCM (3ϫ10 mL). The combined organic ex-
tracts were dried with anhydrous MgSO4, filtered, and concen-
trated in vacuo. The crude product was then purified by flash
chromatography (cyclohexane/AcOEt, 75:25) to give pure com-
pound 9 (95:5 E/Z ratio) as a white solid (750 mg, 77%), m.p. 99–
Eur. J. Org. Chem. 2013, 173–179
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
177

F. Allais et al.
FULL PAPER
102 °C. IR (neat): ν = 1768, 1709, 1640, 1589, 1269, 1192 cm–1. 1H
(13). HRMS (EI): calcd. for C46H55O14 [M + H]+ 831.3592; found
˜
NMR (300 MHz, CDCl3): δ = 7.64 (s, 1 H, 6-H), 7.50 (d, J = 831.3558.
16.2 Hz, 1 H, 7-H), 7.17 (s, 1 H, 2Ј-H), 7.08–6.97 (m, 4 H, 2-H,
tert-Butyl (Z)-3-{5Ј-[(E)-3-(tert-Butoxy)-3-oxoprop-1-en-1-yl]-2Ј,6-
2ЈЈ-H, 6Ј-H, 7Ј-H), 6.90 (d, J = 8.1 Hz, 1 H, 6ЈЈ-H), 6.76 (d, J =
7.8 Hz, 1 H, 5ЈЈ-H), 6.30 (d, J = 15.9 Hz, 1 H, 8-H), 5.34 (s, 1 H,
7ЈЈ-H), 3.91 (s, 3 H, 10-H or 10Ј-H), 3.87 (s, 3 H, 10Ј-H or 10-H),
3.71 (s, 3 H, 10ЈЈ-H), 3.31 (s, 6 H, 8ЈЈ-H), 2.06 (s, 6 H, 12-H, 12Ј-
H), 1.53 (s, 9 H, 14-H or 14Ј-H), 1.36 (s, 9 H, 14Ј-H or 14-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 168.4 (s, C-11 or C-11Ј), 168.3
(s, C-11Ј or C-11), 166.1 (s, C-9), 162.3 (s, C-9Ј), 151.8 (s, C-3 or
C-3Ј), 151.4 (s, C-3Ј or C-3), 149.1 (s, C-4ЈЈ), 146.1 (s, C-3ЈЈ), 142.7
(d, C-7), 142.0 (s, C-4 or C-4Ј), 139.3 (s, C-4Ј or C-4), 138.5 (s, C-
8Ј), 133.2 (s, C-5 or C-5Ј), 133.1 (s, C-5Ј or C-5), 131.8 (s, C-1 or
C-1Ј), 131.3 (s, C-1ЈЈ), 131.0 (s, C-1Ј or C-1), 125.5 (d, C-7Ј), 124.5
(d, C-6 or C-6Ј), 123.1 (d, C-6Ј or C-6), 120.9 (d, C-6ЈЈ), 119.3 (d,
C-2ЈЈ), 114.3 (d, C-8), 113.2 (d, C-5ЈЈ), 110.9 (d, C-2 or C-2Ј), 110.7
(d, C-2Ј or C-2), 103.0 (d, C-7ЈЈ), 82.3 (s, C-13Ј), 80.7 (s, C-13),
56.3 (q, C-10, C-10Ј), 56.0 (q, C-10ЈЈ), 52.8 (q, C-8ЈЈ), 28.2 (q, C-
14Ј, C-14), 20.5 (q, C-12, C-12Ј) ppm. MS (EI+, 50 eV): m/z (%) =
801 (100) [M + Na]+, 796 (93), 747 (88), 733 (32), 677 (10), 517
(29). HRMS (EI): calcd. for C42H50O14Na [M + Na]+ 801.3098;
found 801.3126.
dihydroxy-3Ј,5-dimethoxy-(1,1Ј-biphenyl)-3-yl}-2-{4-[(E)-3-(tert-but-
oxy)-3-oxoprop-1-en-1-yl]-2-methoxyphenoxy}acrylate (11): Sodium
methoxide (60 mg, 0.98 mmol) was added to a solution of 10
(500 mg, 0.60 mmol) in anhydrous methanol (3.5 mL) at room tem-
perature. The mixture was stirred overnight, treated with Amberlyst
IR 120, filtered, and concentrated in vacuo. The crude product was
then purified by flash chromatography (cyclohexane/AcOEt, 6:4)
to give pure compound 11 as a white solid (333 mg, 71%), m.p.
1
125–127 °C. IR (neat): ν = 1702, 1634, 1596, 1257 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 7.54–7.49 (m, 3 H, 7-H, 7ЈЈ-H, 6Ј-H), 7.19
(s, 1 H, 6-H), 7.11–6.61 (m, 5 H, 2-H, 2Ј-H, 2ЈЈ-H, 6ЈЈ-H, 7Ј-H),
6.27–6.18 (m, 3 H, 8-H, 8ЈЈ-H, 5ЈЈ-H), 3.94 (s, 6 H, 10-H, 10Ј-H),
3.80 (s, 3 H, 10ЈЈ-H), 1.52 (s, 18 H, 12-H, 12ЈЈ-H), 1.36 (s, 9 H, 12Ј-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6 (s, C-9 or C-9ЈЈ),
166.5 (s, C-9ЈЈ or C-9), 162.5 (s, C-9Ј), 149.3 (s, C-4ЈЈ), 147.9 (s, C-
3Ј or C-3), 147.4 (s, C-3ЈЈ), 147.1 (s, C-3Ј or C-3), 145.0 (s, C-4 or
C-4Ј), 144.5 (s, C-4Ј or C-4), 143.6 (d, C-7ЈЈ), 143.3 (d, C-7), 139.6
(s, C-8Ј), 129.7 (s, C-1 or C-1Ј), 127.3 (d, C-1Ј or C-1), 127.1 (s, C-
1ЈЈ), 126.4 (d, C-7Ј), 125.0 (s, C-6 or C-6Ј), 124.9 (d, C-6Ј or C-6),
124.0 (s, C-5 or C-5Ј), 123.5 (s, C-5 or C-5Ј), 122.0 (d, C-8ЈЈ), 118.9
(d, C-6ЈЈ), 118.3 (d, C-2ЈЈ), 114.5 (d, C-8), 111.5 (d, C-5ЈЈ), 111.2
(d, C-2 or C-2ЈЈ), 108.9 (d, C-2Ј or C-2), 82.1 (s, C-11Ј), 80.5 (s, C-
11 or C-11ЈЈ), 80.4 (s, C-11 or C-11ЈЈ), 56.4 (q, C-10, C-10Ј or C-
10ЈЈ), 56.3 (q, C-10, C-10Ј or C-10ЈЈ), 56.0 (q, C-10, C-10Ј or C-
10ЈЈ), 28.4 (q, C-12, C-12Ј or C-12ЈЈ), 28.0 (q, C-12, C-12Ј or C-
12ЈЈ) ppm. MS (EI+, 50 eV): m/z (%) = 769 (100) [M + Na]+, 747
(77) [M – H]+, 691 (23), 635 (12), 579 (24). HRMS (EI): calcd. for
C42H51O12 [M + H]+ 747.3381; found 747.3389.
5-[(Z)-3-(tert-Butoxy)-2-{4-[(E)-3-(tert-butoxy)-3-oxoprop-1-en-1-
yl]-2-methoxyphenoxy}-3-oxoprop-1-en-1-yl]-5Ј-[(E)-3-(tert-butoxy)-
3-oxoprop-1-en-1-yl]-3,3Ј-dimethoxy-[1,1Ј-biphenyl]-2,2Ј-diyl Di-
acetate (10): A satd. aq. NH4Cl solution (50 mL) was added to
a solution of 9 (400 mg, 0.51 mmol) in AcOEt (15 mL) at room
temperature. The mixture was then stirred over a 2 h period. The
aqueous layer was then extracted with AcOEt (3ϫ50 mL) and the
combined organic extracts were dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo to give the corresponding alde-
hyde, which was used without further purification.
(Z)-3-{5Ј-[(E)-2-Carboxyvinyl]-2Ј,6-dihydroxy-3Ј,5-dimethoxy-(1,1Ј-
biphenyl)-3-yl}-2-{4-[(E)-2-carboxyvinyl]-2-methoxyphenoxy}acrylic
Acid (A): Trifluoroacetic acid (0.51 mL, 6.72 mmol) was added to
a solution of 11 (251 mg, 0.34 mmol) in anhydrous DCM (3.40 mL)
at room temperature. The mixture was stirred overnight, concen-
trated in vacuo, redissolved in toluene (5 mL), and concentrated in
vacuo (azeotropic removal of TFA) to give pure compound A as a
white solid (195 mg, 99%). The analytical and spectroscopic data
of synthetic A are in good agreement with those reported in the
A solution of (tert-butoxycarbonylmethylene)triphenylphos-
phorane (308 mg, 0.82 mmol) in 1,2-dimethoxyethane (5.3 mL) was
added to a solution of the crude aldehyde in anhydrous 1,2-dime-
thoxyethane (5.3 mL) at room temperature and the mixture was
heated at reflux for 3 h.[28] Water (30 mL) was then added and the
solution was extracted with AcOEt (3ϫ30 mL). The combined or-
ganic extracts were dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. The crude product was then purified by flash
chromatography (cyclohexane/AcOEt, 8:2) to give pure compound
literature,[19a] m.p. 215–220 °C. IR (neat): ν = 2996, 2836, 1694,
˜
1
1629, 1596 cm–1. H NMR (300 MHz, CDCl3): δ = 8.08 (m, 2 H,
10 as a white solid (400 mg, 88%), m.p. 143–147 °C. IR (neat): ν =
˜
OH), 7.62 (d, J = 15.9 Hz, 1 H, 7ЈЈ-H), 7.62–7.57 (m, 2 H, 7-H, 2Ј-
H), 7.49 (s, 1 H, 7Ј-H), 7.44 (s, 1 H, 2ЈЈ-H), 7.35 (s, 2 H, 2-H, 6Ј-
H), 7.14 (d, J = 7.8 Hz, 1 H, 6ЈЈ-H), 7.10 (s, 1 H, 6-H), 6.85 (d, J
= 8.1 Hz, 1 H, 5ЈЈ-H), 6.44 (d, J = 15.6 Hz, 1 H, 8ЈЈ-H), 6.41 (d, J
= 15.6 Hz, 1 H, 8-H), 3.96 (s, 3 H, 10-H, 10Ј-H or 10ЈЈ-H), 3.90 (s,
3 H, 10-H, 10Ј-H or 10ЈЈ-H), 3.79 (s, 3 H, 10-H, 10Ј-H or 10ЈЈ-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.3 (s, C-9), 168.1 (s,
C-9Ј), 164.6 (s, C-9ЈЈ), 150.3 (s, C-4ЈЈ), 149.0 (d, C-3Ј), 148.6 (s, C-
3ЈЈ), 147.5 (s, C-7), 147.1 (s, C-3), 146.1 (s, C-4 and C-4Ј), 145.4 (d,
C-7ЈЈ), 138.6 (s, C-8Ј), 130.1 (s, C-1ЈЈ), 128.7 (d, C-6 or C-6Ј), 128.4
(d, C-6Ј or C-6), 126.7 (s, C-1Ј), 126.1 (d, C-7Ј), 125.8 (s, C-5 or
C-5Ј), 125.7 (s, C-5Ј or C-5), 124.7 (s, C-1), 123.0 (d, C-6ЈЈ), 117.6
(d, C-8ЈЈ), 116.3 (d, C-8), 113.8 (d, C-5ЈЈ), 112.7 (d, C-2Ј), 112.5 (d,
2ЈЈ), 110.1 (d, C-2), 56.6 (q, C-10, C-10Ј or C-10ЈЈ), 56.4 (q, C-10,
C-10Ј or C-10ЈЈ), 56.3 (q, C-10, C-10Ј or C-10ЈЈ) ppm. MS (EI,
50 eV): m/z (%) = 577 (100) [M + Na]+, 288 (33). HRMS (EI):
calcd. for C30H25O12 [M + H]+ 577.1346; found 577.1350.
1769, 1706, 1636, 1589, 1259, 1193 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 7.58–7.48 (m, 3 H, 7-H, 7ЈЈ-H, 6-H), 7.25–6.82 (m, 7
H, 2-H, 2Ј-H, 2ЈЈ-H, 5ЈЈ-H, 6-H, 6Ј-H, 6ЈЈ-H), 6.31 (d, J = 15.3 Hz,
1 H, 8-H or 8ЈЈ-H), 6.29 (d, J = 15.3 Hz, 1 H, 8ЈЈ-H or 8-H), 3.91
(s, 3 H, 10-H or 10Ј-H), 3.87 (s, 3 H, 10Ј-H or 10-H), 3.72 (s, 3 H,
10ЈЈ-H), 2.05 (s, 6 H, 12-H, 12Ј-H), 1.52 (s, 18 H, 14-H, 14ЈЈ-H),
1.36 (s, 9 H, 14Ј-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.3
(s, C-11, C-11Ј), 166.5 (s, C-9ЈЈ), 166.1 (s, C-9), 162.1 (s, C-9Ј),
151.8 (s, C-3 or C-3Ј), 151.5 (s, C-3 or C-3Ј), 149.4 (s, C-4ЈЈ), 147.5
(s, C-3ЈЈ), 143.2 (d, C-7ЈЈ), 142.7 (d, C-7), 141.6 (s, C-4 or C-4Ј),
139.3 (s, C-4Ј or C-4), 138.7 (s, C-8Ј), 133.1 (s, C-5 or C-5Ј), 131.7
(s, C-5Ј or C-5), 131.2 (s, C-1 or C-1Ј), 131.0 (s, C-1Ј or C-1), 130.0
(s, C-1ЈЈ), 125.6 (d, C-7Ј), 124.5 (d, C-6 or C-6Ј), 123.1 (s, C-6Ј or
C-6), 121.9 (s, C-8ЈЈ), 120.9 (s, C-6ЈЈ), 119.1 (d, C-2ЈЈ), 114.9 (d, C-
8), 113.2 (s, C-5ЈЈ), 111.3 (s, C-2 or C-2Ј), 110.7 (s, C-2Ј or C-2),
82.5 (s, C-13Ј), 80.8 (s, C-13 or C-13ЈЈ), 80.5 (s, C-13ЈЈ or C-13),
56.2 (q, C-10, C-10Ј or C-10ЈЈ), 55.9 (q, C-10, C-10Ј or C-10ЈЈ),
28.3 (q, C-14, C-14Ј or C-14ЈЈ), 28.0 (q, C-14, C-14Ј or C-14ЈЈ),
20.5 (q, C-12, C-12Ј) ppm. MS (EI+, 50 eV): m/z (%) = 853 (93) [M
+ Na]+, 848 (100) [M + NH4]+, 831 (56), 775 (16), 719 (13), 663
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra and the numbering of the carbon
atoms in each compound for NMR assignments.
178
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 173–179

Total Synthesis of a Dehydrotrimer of Ferulic Acid
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This work was supported by the CEPIA Department of INRA
(Grant AIC 2011-2012). This work has benefited from the facilities
and expertise of the Small Molecule Mass Spectrometry platform
of IMAGIF (Centre de Recherche de Gif, www.imagif.cnrs.fr). The
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Received: September 28, 2012
Published Online: November 26, 2012
Eur. J. Org. Chem. 2013, 173–179
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