Convergent total synthesis of (±) myricanol, a cyclic natural diarylheptanoid

Article abstract of DOI:10.1039/c8ob02052c

Myricanol 1, a constituent of Myrica species, has been reported to lower the levels of the microtubule-associated protein tau (MAPT), whose accumulation plays an important role in some neurodegenerative diseases, such as Alzheimer's disease (AD). Herein w

Full text of DOI:10.1039/c8ob02052c

Organic &
Biomolecular Chemistry
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Convergent total synthesis of ( ) myricanol,
a cyclic natural diarylheptanoid†
Cite this: Org. Biomol. Chem., 2018,
16, 8859
A. Bochicchio, a,b L. Schiavo,b L. Chiummiento, *a P. Lupattelli,
a
M. Funicello, a G. Hanquet,b S. Choppin b and F. Colobert
*
b
Myricanol 1, a constituent of Myrica species, has been reported to lower the levels of the microtubule-
associated protein tau (MAPT), whose accumulation plays an important role in some neurodegenerative
diseases, such as Alzheimer’s disease (AD). Herein we described a new synthetic route to prepare myri-
canol in 9 steps and 4.9% overall yield starting from commercially available 2,3-dimethoxyphenol and
methyl 3-(4-benzyloxyphenyl)propanoate. The key steps are a cross-metathesis to obtain a linear di-
arylheptanoid intermediate and a Suzuki–Miyaura domino reaction to generate the challenging
macrocycle.
Received 21st August 2018,
Accepted 1st November 2018
DOI: 10.1039/c8ob02052c
rsc.li/obc
Besides these biological properties, the synthesis of such
strained cyclophanes is of high interest.8 The first synthesis
Introduction
The cyclic diaryl heptanoid myricanol 1 was first isolated from of racemic myricanol 1 was reported by Whiting et al.9 and
the stem-bark of Indian Myrica nagi in 1970 by M. J. Begley relied upon an intermolecular coupling between a Grignard
and D. A. Whiting1 and later from different Myrica species: species and an aldehyde to afford the linear diarylheptanoid
Myrica esculenta,2a Myrica rubra2b,c,d and Myrica cerifera.2e,f
in 42% yield and a Ni(0)-mediated coupling of a bis-iodide
Myricanol (1) is a meta, meta bridged diarylheptanoid3 intermediate giving myricanol (1) in ∼10% yield. Thus, start-
bearing a C-11 stereogenic carbinol. Its stereomeric distri- ing from commercially available 1,2,3-trimethoxybenzene and
bution varies from one natural source to another and p-benzyloxypropionaldehyde, Whiting’s synthesis included 14
(+)-aR,11S-myricanol was extracted with 86% enantiomeric steps with 0.21% overall yield.9b–d Dickey et al.6 reported in
excess from Myrica cerifera (bayberry/southern wax myrtle).2f 2015 the second total synthesis of racemic myricanol using
Myricanol displays various biological properties from anti- an aldol condensation to generate the linear diarylheptanoid
oxidant, anti-inflammatory, anti-androgenic to anti-cancer4 and an intramolecular cross coupling between an aryl
and anti-tau.2f,5
boronic acid pinacol ester and an aryl iodide to obtain the
These two last important properties were the subject of macrocycle in 22% yield. Dickey claimed to achieve the total
many recent studies which prove growing interest in this synthesis of racemic myricanol over 7 steps in 2.03% yield,
natural molecule. Dickey et al.2f observed a robust tau-lowering although the advanced starting substrates were not commer-
activity of natural myricanol by investigation of protein tau cially available.
levels in HeLa-C3 cells and recently they attributed this prop-
In relation to a program devoted to the synthesis of biaryl
erty mainly to the (−)-aS,11R-myricanol enantiomer, which was compounds10 and considering the biological importance of
obtained by chiral HPLC resolution of the synthesized racemic such a natural product, only available in small quantities, we
myricanol.6 Considering the antitumoral activities, Dai et al. report herein the third total synthesis of racemic myricanol.
published two important papers showing undoubtedly the Knowing that the macrocyclisation and the formation of the
powerful activity of myricanol to reduce and treat human lung meta, meta heptylene linkage were the key synthetic challenges,
adenocarcinoma A549 cells.4,7
we explored a domino Miyaura arylborylation-intramolecular
Suzuki cross-coupling of the bis-halide intermediate A, which
could result from a cross-metathesis between
(Scheme 1).
2 and B
aDepartment of Science, University of Basilicata, Via dell’Ateneo lucano, 10, 85100
Potenza, Italy
bLaboratoire d’Innovation Moléculaire et Applications (UMR CNRS 7042), Université
de Strasbourg/Université de haute Alsace, ECPM, 25 Rue Becquerel, 67087
Strasbourg, France. E-mail: francoise.colobert@unistra.fr
†Electronic supplementary information (ESI) available: Copy of 1H and 13C NMR
spectra of compounds 7–22. See DOI: 10.1039/c8ob02052c
The arylallyl moiety 2 could be synthesized starting from
2,3-dimethoxyphenol through a Claisen rearrangement while
the homoallylic alcohol could arise from commercially avail-
able methyl 3-(4-benzyloxyphenyl)propanoate through allyl-
boration of the corresponding aldehyde.
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Scheme 3 Preparation of B-type fragment 5.
yield. Importantly this promising result could be exploited
towards an enantioselective synthesis of myricanol (Scheme 4).
In view of the final macrocyclization, iodination in the meta
position of the starting methyl 3-(4-benzyloxyphenyl)propano-
ate was studied. A direct iodination of the allylic alcohol 5 was
not envisaged due to the presence of the allylic alcohol.
Therefore on treatment of methyl 3-(4-benzyloxyphenyl)pro-
panoate with I2, Ag2SO4 followed by transformation of the iodi-
nated ester 6 into the Weinreb amide 7, reduction with
DIBAL-H in CH2Cl2 and addition of the allylborane on the
resulting aldehyde 8 afforded the corresponding iodide 9 in
40% overall yield (Scheme 5).
Scheme 1 Retrosynthesis of myricanol 1.
With the key fragments 2, 5 and 9 in hand, we attempted
cross-metathesis (CM) reaction as depicted in Scheme 6.15
Hence after an extensive optimization study, on modifying the
temperature of addition of the catalyst and the molar ratio
between reagents, the treatment of 2 (4 eq.) with 5 in the pres-
ence of a G-II catalyst (3 mol%) in dichloromethane from
−78 °C to room temperature provided diarylheptanoid 10 in a
gratifying 81% yield.16 Addition of the G-II catalyst at −78 °C
was mandatory to obtain good yields. Excess of partner 2 was
almost recovered after flash chromatography and could be
recycled. In a similar way, cross-metathesis between 2 and the
iodinated 9, in the presence of 15 mol% of G-II catalyst, gave
Results and discussion
The synthesis of fragment 2 commenced with the formation of
the allyl ether 3 in quantitative yield under classical con-
ditions, and subsequent ortho-Claisen rearrangement11 to
install the allylic fragment at C-6 of 2,3-dimethoxyphenol. An
extensive optimization of the reaction conditions was necess-
ary to avoid the competitive para-Claisen rearrangement.11
Finally the use of a Lewis acid (Et2AlCl or Me2AlCl) at 0 °C led
to the desired regioisomer 2 in quantitative yield (Scheme 2).
An important point was the careful acidic workup at low temp-
erature (below 10 °C) in order to avoid the formation of a side-
product due to hydrolysis of the methyl ether at C-2.
On the other hand the preparation of the B type fragment 5
started with the reduction of methyl 3-(4-benzyloxyphenyl)pro-
panoate with DIBAL-H in CH2Cl2 at −78 °C followed by sub-
sequent oxidation with DMP in CH2Cl2 at 25 °C to afford the
crude aldehyde 4 in an excellent yield of 98% which was not
purified for the next step. The addition of either allylmagne-
sium bromide in diethyl ether or allylpinacol borane in THF to
the aldehyde 4 led to the homoallylic alcohol 5 in 78 and 75%
yield, respectively (Scheme 3). Enantioselective allylboration of
4
was
also
tested
using
either
Brown’s
B-allyldiisocamphenylborane12 or Roush’s (R,R)-diisopropyl-
tartrate allylboronate13 giving the enantioenriched homoallylic
alcohol (R)-5 with 74% yield and 86% ee or 64% yield and 78%
ee respectively. Finally a better ee of 90% was reached by allylti-
tanation using Cossy’s (S,S)-Duthaler–Hafner reagent14 in 70%
Scheme 4 Enantioselective allylation of 4.
Scheme 2 Preparation of fragment 2.
Scheme 5 Synthesis of the iodinated B type fragment 9.
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Scheme 7 Oxidative macrocyclization of 16.
Therefore we decided to explore the intramolecular Suzuki
cross coupling reaction. Accordingly we tried to synthesize the
corresponding precursors bearing a boronic ester and a halide.
Starting from 16, palladium-catalysed borylation afforded
smoothly the pinacol boronic ester 22 which was then sub-
jected to the iodination with NIS, CF3COOH in CH3CN.
Unfortunately only a trace amount of the iodinated compound
23 was obtained. We suspected the ipso-substitution of the
boronic acid with iodine.19 Moreover a chemoselective mag-
nesium–iodine exchange on substrate 19 followed by addition
of the borane species did not allow one to obtain the corres-
ponding boronic ester 24 (Scheme 8).
Consequently we turned our attention to the domino
Miyaura arylborylation-intramolecular Suzuki cross-coupling
reaction20 inspired by the macrocyclization reported by Zhu21
involving such a domino process in the frame of the total syn-
thesis of biphenomycin A, a 15-membered meta, meta cyclo-
phane. As depicted in Scheme 9 (1), the desired product was
obtained in 45% yield after numerous attempts which clearly
demonstrated the delicate outcome of this reaction and that
little variations of the reaction conditions could drastically
lower the yield of the cyclization to 10% or trace amounts of
products. Three years later Usuki22 en route to the total syn-
thesis of acerogenin E and K applied Zhu’s conditions for the
macrocyclization of a di-iodo linear diarylheptanoid and they
obtained the 13-membered meta, meta cyclophane in 35%
yield showing again in all attempts performed, a strong influ-
ence of the reaction conditions and the molarity of this crucial
macrocyclization (Scheme 9 (2)). Such a Suzuki–Miyaura
domino process was also employed by Hutton23 in the total
synthesis of mycocyclosin.
Scheme 6 Synthesis of the linear diarylheptanoids 15–21.
rise to alkene 11 in an excellent 82% yield. Subsequent
alkene reduction and debenzylation of 10 H2, Pd/C in MeOH
gave 12 which was protected as benzyl ether 15 and dibromi-
nated with NBS to give 18. On the other hand chemoselective
hydrogenation of the C–C double-bond of 10 and 11 was per-
formed by reduction with 2-nitrobenzenesulfonylhydrazide,17
obtained in situ by mixing hydrated hydrazine and 2-nitro-
benzenesulfonylchloride, to afford 13 and 14 in excellent
yield which were subsequently benzylated to ethers 15 and
16, respectively. This protocol could lead to different protec-
tions of the three hydroxyl functions on the linear diarylhep-
tanoid; indeed acetylation of 13 afforded 17 in quantitative
yield. Subsequent functionalization of 15 and 16 by NBS in
CH3CN afforded the dibromo-18 and the iodo-bromo-diaryl-
heptanoid 19 respectively, while treatment of 16 and 17 with
NIS resulted in the formation of the bis-iodo 20 and 21
respectively (Scheme 6).
Having in hand the linear diarylheptanoids 15–21, the chal-
lenging macrocyclization step was explored. In a first attempt
drawing inspiration from an intramolecular biaryl macrocycli-
zation involving C–H arylation with arylhalide reported by
Fagnou18 in the total synthesis of allocolchicine, we applied
the same reaction conditions, i.e. Pd(OAc)2, DavePhos with
K2CO3 in DMA, to the oxidative macrocyclization of the iodi-
nated diarylheptanoid 16. Unfortunately we obtained the de-
iodinated product together with some other unidentified pro-
ducts (Scheme 7).
Scheme 8 Synthesis of Suzuki–Miyaura cross-coupling precursors.
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ing from the bis-iodo 21 bearing two acetoxy groups, myricanol
was obtained after successive deacetylation (Na in MeOH) and
debenzylation in a comparable yield of 12% over 3 steps.
Finally our macrocyclization’s yields are in agreement with
the one obtained by Whiting9 in the Ni(0) catalyzed process
(7.3%). Importantly the crucial difference between Zhu’s and
Usuki’s studies and ours which could explain the decrease of
the macrocyclization’s yield is that their linear diarylhepta-
noids are symmetrical exhibiting the same electronic pro-
perties of the two aryl moieties involved in the biaryl coupling.
Scheme 9 Domino-Suzuki–Miyaura macrocyclization by Zhu and
Usuki.
Conclusion
In conclusion we have reported herein the total synthesis of
racemic myricanol in 4.9% yield over 9 steps from methyl 3-(4-
benzyloxyphenyl)propanoate. This strategy involved a conver-
gent access to the linear diarylheptanoids through a cross-
metathesis in excellent yields and a Suzuki–Miyaura intra-
molecular cross-coupling reaction to perform the final macro-
cyclization. This third total synthesis of racemic myricanol can
undoubtedly compete with the two previous one described by
Whiting9b and Dickey.6
Taking into account these encouraging results, we decided
to apply the domino Miyaura arylborylation-intramolecular
Suzuki cross-coupling reaction on our linear diarylheptanoids
to obtain the 13-membered meta, meta cyclophane of myrica-
nol. Table 1 summarizes the trials starting from the different
di-halogenated substrates with different protections of the
hydroxyl groups. With the di-brominated substrate 18 bearing
three benzyloxy groups following exactly the conditions
reported by Zhu i.e. PdCl2(dppf), B2(pin)2, KOAc in DMSO
(0.002 M) at 80 °C, we did not observe the formation of the
macrocycle (Table 1, entry 1). However replacing KOAc by
NaOAc led to the desired 13-membered ring of benzylated myr-
icanol which after quantitative debenzylation afforded myrica-
Experimental section
Materials, chemicals, and equipment
Commercially obtained reagents and solvents were used as
received from Sigma Aldrich, TCI and Alfa Aesar. Et2O, 1,4-
dioxane and THF were dried by distillation over sodium/benzo-
phenone. DCM was dried over CaH2 under argon.
Diisopropylamine and triethylamine were dried over KOH
under argon. Melting ranges (M.p.) given were found to be
reproducible after recrystallization.
NMR spectra were recorded on a Bruker Avance (400 MHz
and 300 MHz) and on a Varian (400 MHz and 500 MHz).
Samples were prepared using CDCl3. Chemical shifts were
referred to 7.27 ppm (1H) and 77.00 ppm (13C) for CDCl3.
Chemical shifts are expressed in parts per million (ppm) and
coupling constants J in hertz. Multiplicities were abbreviated
as s (singlet), bs (broad singlet) d (doublet), t (triplet),
q (quartet) and m (multiplet) for 1H-NMR. For 13C-NMR q is
referred to a quaternary carbon.
1
nol 1 in 10% yield over 2 steps (Table 1, entry 2). The H-NMR
spectra were identical to the one reported for the myricanol
natural product.2f Encouraged by this result, an extensive
optimization study by changing the solvent (dioxane), the
boron source (PinB-H) and the temperature (80 to 100 °C) did
not improve the reactivity. Moreover no macrocyclization
occurred starting from the bromo-iodo or the bis-iodo sub-
strates 19 and 20 (Table 1, entries 3 and 4). Surprisingly, start-
Table 1 Intramolecular Suzuki–Miyaura process
Purifications were performed by column chromatography on
silica gel by using MERCK silica (70–230 mesh, Merck).
Reactions were monitored by analysis over thin layer chromato-
graphy (TLC) with Alugram® Xtra SIL G/UV (Macherey-Nagel)
plates and 0.25 mm Merck silica-gel (60-F254) plates. TLC was
visualized by UV fluorescence at 250 nm and revealed with a solu-
tion of anisaldehyde (5.1 mL of p-anisaldehyde, 2.1 mL of acetic
acid, 6.9 mL of concentrated sulfuric acid, 186 mL of EtOH 95%).
Mass spectra were recorded by using a Hewlett Packard GC/
MS 6890-5973 with an EI source. The angles of rotation were
measured on a PerkinElmer Polarimeter 341 and denoted as
specific rotations: [α]2D0.
Boron
source
Base
10 equiv.
Solvent
(0.002 M)
Yield
of 1
Entry
Substrate
T, °C
1
2
3
4
5
18
18
19
20
21
(BPin)2
(BPin)2
(BPin)2
(BPin)2
(BPin)2
KOAc
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
100
100
80
—
10%
—
Trace
12%
NaOAc
NaOAc
NaOAc
KOAc
Reagent and conditions: Substrate (1 equiv.), boron source (1.2 equiv.),
base (10 equiv.), solvent (0.002 M), 24 h.
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1-(Allyloxy)-2,3-dimethoxybenzene (3).11 To a solution of 2,3- quenched with water and extracted with DCM. The organic
dimethoxyphenol (46.3 mmol, 9.0 g) in acetone (185 mL), layers were dried on Na2SO4, filtered and concentrated under
K2CO3 (92.6 mmol, 12.8 g) was added and after 10 min allyl reduced pressure to give quantitatively aldehyde 4 (observed
bromide (55.5 mmol, 4.72 mL) was added. The reaction on GC-MS). The aldehyde was recovered as a dense viscous
mixture was stirred at reflux for 5 h until complete transform- white liquid. The crude was rapidly characterized with
ation of the starting phenol and then quenched with H2O and 1H-NMR and immediately put in a reaction chamber or
extracted with EtOAc (3 × 50 mL mmol−1). The combined stocked in the freezer at −20 °C. Rf = 0.4 (cyclohexane/EtOAc
organic extracts were washed with brine, dried over Na2SO4, fil- 8 : 2), 1H NMR (400 MHz, CDCl3): δ 2.74 (t, J = 7.6 Hz, 2H,
tered and concentrated under vacuum. The crude reaction was CH2), 2.88 (t, J = 7.6 Hz, 2H, CH2), 5.04 (s, 2H, CH2–Bn), 6.89
purified through a silica pad to afford the desired 3 (9.0 g, (d, J = 8.4 Hz, 2H, Ar–H), 7.09 (d, J = 8.5 Hz, 2H, Ar–H), 7.42
46.3 mmol, 99% yield) as a brown oil. Rf = 0.5 (petroleum (m, 5H, Bn–H), 9.81 (s, 1H, CHO). Identity was confirmed by
ether/Et2O 8 : 2); 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H, the literature data.24
OCH3), 3.87 (s, 3H, OCH3), 4.59 (d, J = 5.2 Hz, 2H, Ar–OCH2),
5.26 (dd, 1H, Jcis = 10.4 Hz, 0.8 Hz, CH-allyl), 5.39 (dd, Jtrans
1-(4-(Benzyloxy)phenyl)hex-5-en-3-ol (5). Procedure A: To a
solution of crude aldehyde 4 (4.08 mmol, 0.98 g) in THF
=
17.2 Hz, 0.8 Hz, 1H, CH-allyl), 6.04 (m, 1H, CH-allyl), 6.57 (d, (13.6 mL) was added at −78 °C, dropwise and under argon, a
J = 8.4 Hz, 2H, 2Ar–H), 6.94 (t, J = 8.0 Hz, 1H, Ar–H); 13C NMR solution of allylmagnesium bromide (4.04 mmol, 1 M in
(100 MHz, CDCl3): δ 56.1, 60.8, 69.9, 105.5, 107.2, 117.4, 123.4, diethyl ether). The solution was stirred for 2 h and allowed to
133.5, 138.7 (q), 152.5 (q), 153.7 (q); GC-MS(EI) m/z 194 [M]+ warm to r.t. The mixture was then quenched with water
(100), 179 (10), 153 (80), 138 (10), 125 (100), 110 (70), 95 (50); (40 mL) and stirred for 10 minutes. The mixture was extracted
anal. C 68.05, H 7.24%, calcd for C11H14O3, C 68.02, H 7.27%.
6-Allyl-2,3-dimethoxyphenol (2).11 To
solution of
with DCM (3 × 40 mL) and the organic layers were dried on
Na2SO4 and concentrated under vacuum. The crude product
a
3
(5.50 mmol, 1.1 g) in dry hexane (10 mL) was added dropwise was purified by column chromatography on silica gel (cyclo-
a 1 M solution of Et2AlCl in hexane (7.7 mmol, 7.7 mL) at 0 °C hexane/EtOAc 4 : 1) to obtain product 5 (0.86 g, 75% yield) as a
and under an inert atmosphere. The mixture was strongly white solid.
stirred at 0 °C for 1 h 15 min. Formation of an orange solid
Procedure B: To a solution of allyl boronic acid pinacol
(gum) was observed. The reaction was quenched by diluting ester (4.08 mmol) in THF (4 mL) a solution of crude aldehyde
the mixture with hexane (200 mL) and pouring it into a cold 4 (4.08 mmol, 0.98 g) in THF (13.6 mL) was added under
aqueous solution of HCl solution (4 M, 350 mL). Dissolution argon. The solution was stirred at room temperature for 5 h.
of the orange gum was observed. The mixture was extracted The reaction mixture was then quenched with water (40 mL)
with EtOAc (3 × 200 mL), dried over Na2SO4 and evaporated and stirred for 10 minutes. The mixture was extracted
under reduced pressure to dryness to obtain the product 2 with DCM (3 × 40 mL) and the organic layers were dried on
(1.1 g, 99%) as a brown oil. Rf = 0.5 (petroleum ether/Et2O Na2SO4 and concentrated under vacuum. The crude product
8 : 2); 1H NMR (400 MHz, CDCl3): δ 3.34 (d, J = 6.0 Hz, 2H, was purified by column chromatography on silica gel
CH2-allyl), 3.84 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.02 (d, Jcis
=
(cyclohexane/EtOAc, 4 : 1) to obtain product 5 (0.90 g, 78%
10.4 Hz, 1H, CH-allyl), 5.04 (d, Jtrans = 17.0 Hz, 1H, CH-allyl), yield) as a white solid. M.p. 62–63 °C; Rf = 0.5 (cyclohexane/
5.88 (bs, 1H, OH), 5.96 (m, 1H, CH-allyl), 6.42 (d, J = 8.4 Hz, EtOAc 6 : 4); 1H NMR (400 MHz, CDCl3): δ 1.76 (m, 2H,
1H, Ar–H), 6.78 (d, J = 8.4 Hz, 1H, Ar–H); 13C NMR (100 MHz, ArCH2CH2CHOH), 2.18 (m, 1H, OHCHCH2CHvCH2), 2.34 (m,
CDCl3): δ 33.7, 56.1, 61.1, 103.6, 115.5, 119.4 (q), 124.3, 135.6, 1H, OHCHCH2CHvCH2), 2.63 (m, 1H, ArCH2), 2.75 (m, 1H,
137.1 (q), 147.4 (q), 150.9 (q); GC-MS(EI) m/z 194 [M]+(100), ArCH2), 3.67 (m, 1H, CHOH), 5.05 (s, 2H, CH2–Bn), 5.15 (dd,
179 (20), 163 (14), 147 (40); anal. C 68.05, H 7.24%, calcd for J = 12 Hz, J = 2 Hz, 2H, CHvCH2), 5.82 (m, 1H, CHvCH2),
C11H14O3, C 68.02, H 7.27%.
6.91 (d, J = 8.5 Hz, 2H, Ar–H), 7.12 (d, J = 8.5 Hz, 2H, Ar–H),
3-(4-(Benzyloxy)phenyl)propanal (4). To a solution of methyl 7.37 (m, 5H, Bn–H); 13C NMR (100 MHz, CDCl3): δ 31.1, 38.6,
3-(4-benzyloxyphenyl)propanoate (3.70 mmol, 1.0 g) in DCM 42.0, 69.9, 70.1, 118.2, 114.8, 127.4, 127.8, 128.5, 129.3, 134.4
(30 mL) DIBAL-H (7.4 mL, 1 M in toluene) was added dropwise (q), 134.6, 137.3 (q), 157.1 (q); GC-MS (EI) m/z 282 [M]+(30),
at −78 °C. The reaction mixture was stirred at −78 °C for 3 h 191(40), 91(100), anal. C 80.85, H 7.87%, calcd for C19H22O2,
before quenching with a saturated aqueous solution of diethyl C 80.82, H 7.85%. Identity was confirmed by the literature
tartrate sodium potassium (40 mL) at −78 °C. The temperature data.25
was allowed to warm to r.t. and the mixture was stirred all
(R)-1-(4-(Benzyloxy)phenyl)hex-5-en-3-ol (5). Method A of
night long. The phases were separated, the aqueous layer was Brown’s allylation:12 To a solution of (−)-B-chlorodiisopino-
extracted with DCM, and the combined organic layers were camphenylborane (0.55 mmol, 0.173 g) in dry THF (2.5 mL)
washed with brine, dried over Na2SO4, filtered and concen- allylmagnesium bromide (0.55 mmol, 0.55 mL, 1 M in Et2O)
trated under reduced pressure to obtain aldehyde 4 in a was added dropwise at −78 °C. The mixture was stirred at this
mixture with the corresponding alcohol (1 : 1 evaluated by temperature for 1 h and then warmed to room temperature
1H-NMR). The crude product (0.98 g) was dissolved in DCM within 1 h 20 min. The reaction mixture was cooled down to
(15 mL) and Dess–Martin periodinane (3.70 mmol, 1.57 g) was −90 °C and a solution of aldehyde 4 (0.42 mmol, 0.10 g) in
added at room temperature. The mixture was stirred for 2 h, THF (0.20 mL, 2 M) was added dropwise. The mixture was
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maintained at this temperature during the addition. The reac- mixture was stirred at −78 °C for 5.5 h after which it was
tion mixture was stirred for 1 h at −90 °C and then allowed to treated with 4 mL of a saturated aqueous solution of NH4Cl
warm to r.t. within 1 h. The mixture was quenched with 30% and warmed to room temperature for 15 h. It was filtered over
H2O2 (2 mL) and an aqueous solution of NaOH (2 M, 2 mL) at Celite and extracted with ether (3 × 7 mL). The combined
0 °C and stirred for 1.5 h at r.t. and then extracted with EtOAc organic phases were washed with brine (10 mL), dried over
(3 × 10 mL), washed with water (20 mL) and brine (20 mL). Na2SO4, and evaporated under reduced pressure to give a
Organic layers were dried over Na2SO4 and evaporated under solid. This crude solid was stirred with pentane (5 mL) and fil-
reduced pressure to dryness. The crude product was purified tered. The filtrate was evaporated under reduced pressure to
by silica gel chromatography (cyclohexane to cyclohexane/ give a white solid which was purified by silica gel column
EtOAc 4 : 1) to obtain the product as a white solid (0.065 g, chromatography (cyclohexane to cyclohexane/EtOAc, 4 : 1)
74% yield, 86% ee). The optical purity was determined by affording the desired product 5 (0.047 g, 90% ee, 70% yield).
HPLC chiral chromatography using a CHIRACEL OD-H column
(250 mm, 4.6 mm, 3.5 µm), eluent: 80 : 20 hexane/isopropanol,
Methyl 3-(4-(benzyloxy)-3-iodophenyl)propanoate (6)
flow: 0.5 mL min−1, sample concentration: 1 mg mL−1, injec-
tion volume: 20 µL, retention time: (S: 12.3 min, R: 14.5 min).
Methyl 3-(4-(benzyloxy)phenyl)propanoate (8.17 mmol, 2.2 g),
Method B of Roush’s allylation:13 A solution of triisopropyl I2 (8.17 mmol, 1.0 g) and Ag2SO4 (8.17 mmol, 2.5 g) were dis-
borate (4.33 mmol, 1 mL) in dry Et2O (1.1 mL) and allylmagne- solved in DCM (32 mL, 0.25 M) and stirred at room tempera-
sium bromide in Et2O (4.4 mL, 1 M) was added dropwise sim- ture until halogenation, monitored by TLC was completed. The
ultaneously, but separately, to 1.1 mL of dry Et2O at −78 °C. solution was filtered, washed with a saturated aqueous solu-
This mixture was stirred for 0.5 h at −78 °C, allowed to warm tion of Na2S2O3 (2 × 16 mL), H2O (2 × 16 mL) and brine (2 ×
to room temperature and stirred for 3 h. The slurry was 16 mL), dried over Na2SO4 and concentrated under reduced
recooled to 0 °C, and then an aqueous solution of HCl (4 mL, pressure to give the pure final product 6 (2.91 g, 90% yield) as
1N solution saturated with NaCl) was added dropwise. The a white solid. M.p. = 67–70 °C, Rf = 0.5 (cyclohexane/EtOAc
mixture was stirred for 15 min at 0 °C and warmed to room 6 : 5) 1H NMR (400 MHz, CDCl3): δ 2.59 (t, J = 7.8 Hz, 2H, CH2),
temperature, and stirring was continued for 15 min. The 2.86 (t, J = 7.8 Hz, 2H, CH2), 3.68 (s, 3H, OCH3), 5.13 (s, 2H,
organic layer was separated and directly treated with (+)-(R,R)- CH2–Bn), 6.78 (d, J = 8.5 Hz, 2H, Ar–H), 7.11 (dd, Jortho = 8.5
diisopropyl L-tartrate (DIPT) (4.74 mmol, 1 mL). The aqueous Hz, Jmeta = 2.2 Hz, 2H, Ar–H), 7.38 (m, 5H, CH–Bn), 7.65 (dd,
phase was extracted with dry DCM/Et2O solution (1 : 5, 3 × Jortho = 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 29.5, 35.6,
6 mL) and transferred to the Schlenk tube containing first 51.6, 76.6, 86.8 (q), 112.7, 127.0, 127.8, 128.5, 129.2, 135.1 (q),
organic layer and (R,R)-DIPT. The combined organic layers 136.6 (q), 139.2 (q), 155.8 (q), 173.1 (q); GC-MS(EI) m/z 396
were stirred for 1 h and anhydrous Na2SO4 was added. The [M]+(40), 305 (60), 270 (30), 91 (100); anal. C 51.57, H 4.39%,
mixture was stirred for 1 night at r.t. It was then evaporated calcd for C17H17IO3, C 51.53, H 4.32%. Identity was confirmed
under reduced pressure to give a clear, slightly yellow, semi by the literature data.26
viscous liquid (1.23 g) of 4,5-bis(propan-2-yl)(4R,5R)-2-(prop-2-
3-(4-(Benzyloxy)-3-iodophenyl)-N-methoxy-N-methylpropan-
(7). N,O-Dimethylhydroxylamine hydrochloride
en-1-yl)-1,2,3-dioxaborolane-4,5-dicarboxylate. solution of amide
A
the just prepared crude product in dry toluene (0.8 mL, 0.22 g (37.86 mmol, 3.69 g) was dissolved in dry DCM (144 mL)
mL−1) was treated with 4 Å molecular sieves (powder, 90 mg) under an inert atmosphere. Then, a solution of AlMe3
and was stirred for 15 min. Then, it was cooled to −78 °C, and (37.86 mmol, 18.93 mL, 2 M in toluene) was added dropwise at
a solution of starting aldehyde 4 (0.62 mmol, 0.150 g) in dry room temperature. The mixture was stirred for 30 min and a
toluene (1 mL, 0.62 M) was added dropwise. The mixture was solution of ester 6 (12.62 mmol, 5.0 g) in dry DCM (54 mL) was
stirred for 5 h at the same temperature. The reaction mixture added to the mixture. The mixture was heated to reflux over-
was quenched with NaOH (5 mL, 1 M) and 5 mL of Et2O. The night becoming yellow. The reaction was slowly hydrolysed
two phase mixtures were stirred for 30 min at room tempera- (after 20 h) with an aqueous solution of HCl (0.5 M, 40 mL).
ture to hydrolyse DIPT and then were separated extracting with The aqueous layer was extracted with DCM (3 × 40 mL). The
Et2O (3 × 7 mL). The organic layer was dried over Na2SO4, fil- organic layers were washed with a saturated aqueous solution
tered and evaporated under reduced pressure to dryness to of NaHCO3, dried on Na2SO4 and evaporated under reduced
give a crude product. The crude was purified twice by chrom- pressure. The crude product was purified by column chromato-
atography (cyclohexane to cyclohexane/EtOAc, 4 : 1) affording graphy on silica gel (cyclohexane/EtOAc 3 : 2) to obtain the
the desired product 5 (0.11 g, 78% ee) in 64%yield.
pure product 7 (4.13 g, 77% yield) as a transparent oil. Rf =
Method C for allyltitanation:14 Allylmagnesium bromide in 0.57 (cyclohexane/EtOAc 4 : 6); 1H NMR (400 MHz, CDCl3): δ
Et2O (0.28 mmol, 0.28 mL, 1 M solution) was added dropwise 2.69 (t, J = 7.5 Hz, 2H, CH2), 2.86 (t, J = 7.5 Hz, 2H, CH2), 3.17
at 0 °C under argon to a solution of (R,R) Duthaler–Hafner (s, 3H, N–CH3), 3.61 (s, 3H, N–OCH3), 5.12 (s, 2H, CH2–Bn),
reagent (0.33 mmol, 0.20 g), in dry Et2O (4 mL, 0.083 M). After 6.77 (d, J = 8.5 Hz, 2H, Ar–H), 7.13 (dd, Jortho = 8.5 Hz, Jmeta
=
stirring for 1.5 h at 0 °C, the slightly orange suspension was 2.0 Hz, 2H, Ar–H), 7.38 (m, 5H, Bn–H); 7.66 (d, Jmeta = 1.9 Hz,
cooled to −78 °C and starting aldehyde 4 (0.24 mmol, 0.057 g) 1H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 29.3, 32.2, 33.7, 61.3,
dissolved in dry ether (0.75 mL, 0.32 M) was added. The 71.0, 86.8 (q), 112.7, 127.0, 127.9, 128.5, 129.5, 136.0 (q), 136.7
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(q), 139.3, 155.7 (q), 173.6 (q); anal. C 50.79, H 4.74, N 3.27%, generation Grubbs catalyst (3 or 15 mol%) in dry DCM (0.02
calcd for C18H20INO3, C 50.84, H 4.74, N 3.29%. M) was added dropwise, under an Ar atmosphere at −78 °C.
3-(4-(Benzyloxy)-3-iodophenyl)propanal (8). To a solution of The reaction mixture was stirred at −78 °C and allowed to
the previously synthesized Weinreb amide 7 (2.35 mmol, 1.0 g) warm to r.t. for 1 day under stirring. The mixture was evapor-
in DCM (20 mL) was added DIBAL-H (4.70 mL, 1 M in toluene) ated and the crude was purified by column chromatography
dropwise at −78 °C. The mixture was stirred at −78 °C for 3 h on silica gel (from pure cyclohexane to cyclohexane/EtOAc, to
before quenching with a saturated aqueous solution of diethyl 3 : 2).
tartrate sodium potassium (30 mL) at −78 °C. The temperature
6-(7-(4-(Benzyloxy)phenyl)-5-hydroxyhept-2-en-1-yl)-2,3-dimetho-
was allowed to warm to r.t. and the mixture was stirred all xyphenol (10). The desired product 10 (1.12 g, 81% yield) was
night long. The phases were separated, the aqueous layer was obtained according to the general procedure after 24 h from
extracted with DCM, and the combined organic layers were allylphenol 2 (13.0 mmol, 2.5 g), homoallylic alcohol 5
washed with brine, dried over Na2SO4, filtered and concen- (3.22 mmol, 0.90 g) and
trated under reduced pressure to give the crude aldehyde 8 (0.097 mmol, 0.082 g). The addition of catalyst was done rigor-
(86% yield evaluated by 1H-NMR). ously at −78 °C. Rf = 0.35 (cyclohexane/EtOAc 8 : 2); 1H NMR
3 mol% of Grubbs catalyst
The aldehyde was recovered as a dense viscous white liquid (400 MHz, CDCl3): δ 1.73 (m, 2H, ArCH2CH2), 2.21 (m, 1H,
easily degradable at room temperature and not purifiable by OHCHCH2CHvCH), 2.27 (m, 1H, OHCHCH2CHvCH), 2.63
column chromatography. The crude product was rapidly (m, 1H, ArCH2CH2), 2.75 (m, 1H, ArCH2CH2), 3.32 (d, J =
1
characterized with H-NMR and immediately put in a reaction 6.4 Hz, 2H, ArCH2CHvCH), 3.62 (m, 1H, OHCH), 3.84 (s, 3H,
chamber or stocked in the freezer at −20 °C. A not clean OCH3), 3.89 (s, 3H, OCH3), 5.05 (s, 2H, OCH2Bn), 5.46 (m, 1H,
13C-NMR was also obtained, and the characteristic peaks of CHvCH), 5.72 (m, 1H, CHvCH), 5.88 (s, 1H, OH), 6.42 (d, J =
the aldehyde were individuated. Rf = 0.35 (cyclohexane/EtOAc = 8.4 Hz, 1H, Ar–H), 6.77 (d, J = 8.4 Hz, 1H, Ar–H), 6.90 (d, J = 8.4
8 : 2); 1H NMR (400 MHz, CDCl3): δ 2.75 (t, J = 7.6 Hz, 2H, Hz, 2H, Ar–H), 7.11 (d, J = 8.4 Hz, 2H, Ar–H), 7.38 (m, 5H,
CH2), 2.87 (t, J = 7.6 Hz, 2H, CH2), 5.13 (s, 2H, CH2–Bn), 6.78 Bn–H); 13C NMR (100 MHz, CDCl3): δ 31.1, 32.9, 38.6
(d, J = 8.4 Hz, 2H, Ar–H), 7.10 (dd, Jortho = 8.5 Hz, Jmeta = 2.2 Hz, (OHCHCH2CH2Ar), 40.7 (OHCHCH2CHvCH), 55.8 (OCH3),
2H, Ar–H), 7.39 (m, 3H, Bn–H), 7.49 (d, J = 7.0 Hz, 2H, Bn–H), 60.9, 70.1, 73.1, 103.6, 114.8, 119.5 (q), 124.1, 126.7, 127.6,
7.65 (d, Jmeta = 2.2 Hz, 1H, Ar–H), 9.81 (s, 1H, CHO); 13C NMR 128.0, 128.6, 129.3, 132.8, 134.6 (q), 137.4 (q), 137.4 (q), 147.2
(100 MHz, CDCl3): δ 26.7, 45.3, 71.0, 87.0 (q), 112.8, 127.0, (q), 150.8 (q), 157.2 (q); anal. C 80.00, H 7.21%, calcd for
127.9, 128.5, 129.3, 134.9 (q), 136.5 (q), 139.2, 155.8 (q,), 201.1 C28H32O5, C 74.97, H 7.19%.
(q). GC-MS (EI) m/z 366 [M]+(10), 276(25), 91 (100).
(E)-6-(7-(4-(Benzyloxy)-3-iodophenyl)-5-hydroxyhept-2-en-1-
1-(4-(Benzyloxy)-3-iodophenyl)hex-5-en-3-ol (9). To a solution yl)-2,3-dimethoxyphenol (11). The desired product 11 (0.60 g,
of allyl boronic acid pinacol ester (2.73 mmol, 0.53 mL) in THF 82% yield) was obtained according to the general procedure,
(2.73 mL, 1 M) a solution of crude aldehyde 8 (2.73 mmol, after 24 h from allylphenol 2 (5.15 mmol, 1.0 g), homoallylic
1.0 g) in THF (9.10 mL, 0.3 M) was added under argon. The alcohol 9 (1.28 mmol, 0.52 g) and 15 mol% of Grubbs catalyst
solution was stirred at room temperature for 5 h. The mixture (0.19 mmol, 0.163 g). The addition of catalyst was done
was then quenched with water (27 mL) and stirred for rigorously at −78 °C. Rf = 0.3 (cyclohexane/EtOAc 8 : 2);
10 minutes. The reaction mixture was extracted with DCM (3 × 1H NMR (400 MHz, CDCl3): δ 1.82–1.65 (m, 2H, ArCH2CH2),
27 mL) and the organic layers were dried on Na2SO4 and con- 2.09 (m, 1H, OHCHCH2CHvCH), 2.37–2.20 (m, 1H,
centrated under vacuum. The crude product was purified by OHCHCH2CHvCH), 2.81–2.53 (m, 2H, ArCH2CH2), 3.34 (d, J =
column chromatography on silica gel (cyclohexane/EtOAc, 6.4 Hz, 2H, ArCH2CHvCH), 3.61 (m, 1H, OHCH), 3.85 (s, 3H,
4 : 1) to obtain product 9 (0.80 g, 72% yield) as a white solid. OCH3), 3.90 (s, 3H, OCH3), 5.13 (s, 2H, OCH2Bn), 5.57–5.40 (m,
M.p. = 66–68 °C Rf = 0.5 (cyclohexane/EtOAc 6 : 4) 1H NMR 1H, CHvCH), 5.83–5.66 (m, 1H, CHvCH), 5.97 (s, 1H, OH),
(400 MHz, CDCl3): δ 1.74 (m, 2H, ArCH2CH2CHOH), 2.16 (m, 6.43 (d, J = 8.4 Hz, 1H, Ar–H), 6.78 (d, J = 8.4 Hz, 2H, Ar–H),
1H, OHCHCH2CHvCH2), 2.29 (m, 1H, OHCHCH2CHvCH2), 7.09 (dd, Jortho = 8.4 Hz, Jmeta = 2.1 Hz, 1H, Ar–H), 7.45–7.29 (m,
2.61 (m, 1H, ArCH2), 2.70 (m, 1H, ArCH2), 3.65 (m, 1H, 3H, Bn–H), 7.51 (d, J = 7.4 Hz, 2H, Bn–H), 7.66 (d, Jmeta = 2.1
CHOH), 5.12 (s, 2H, CH2–Bn), 5.12 (dd, J = 12 Hz, J = 2 Hz, 2H, Hz, 1H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 31.6, 32.9, 38.3,
CHvCH2), 5.80 (m, 1H, CHvCH2), 6.77 (d, J = 8.5 Hz, 2H, Ar– 40.7, 55.8, 60.9, 69.8, 71.0, 86.8 (q), 103.5, 112.7, 119.5 (q),
H), 7.10 (dd, Jortho = 8.5 Hz, Jmeta = 2.1 Hz, 2H, Ar–H), 7.40 (m, 124.0 (q), 126.5, 127.0, 127.8, 128.5, 129.3, 132.9, 135.5 (q),
5H, Bn–H), 7.65 (d, Jmeta = 2.1 Hz, 1H, Ar–H); 13C NMR 136.7 (q), 136.9 (q), 139.2, 147.2 (q), 150.8 (q), 155.4 (q); anal.
(100 MHz, CDCl3): δ 31.0, 38.4, 42.1, 69.7, 71.0, 86.9 (q), 112.7, C 58.55, H 5.45%, calcd for C28H31IO5, C 58.54, H 5.44%.
118.5, 127.0, 127.8, 128.5, 129.3, 134.5 (q), 136.7, 136.7 (q),
6-(5-Hydroxy-7-(4-hydroxyphenyl)heptyl)-2,3-dimethoxyphenol
139.3, 155.5 (q); anal. C 55.92, H 5.13%, calcd for C19H22IO2, (12). Substrate 10 (0.37 mmol, 0.2 g) was treated with Pd/C
C 55.89, H 5.18%.
(5%) (0.037 mmol, 0.079 g, 10 mol%) in MeOH (0.74 mL, 0.5
M) in H2. The reaction was monitored by TLC and after 18 h
the mixture was passed through a pad of Celite and washed
General procedure of cross-metathesis reaction
To a solution of homoallylic alcohol (5 or 9, 1 eq.) and the with MeOH. The solvent was removed under vacuum to afford
allylphenol 3 (4 eq.) in dry DCM (0.08 M), a solution of second the pure desired product 12 (0.134 g, 99% yield); Rf = 0.35
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(cyclohexane/EtOAc 6 : 4); 1H NMR (400 MHz, CDCl3): δ General procedure of benzylation of compounds 12 and 14
1.67–1.35 (m, 8H, CH2), 2.66–2.52 (m, 3H, ArCH2CH2),
2.78–2.64 (m, 1H, ArCH2CH2), 3.67–3.57 (m, 1H, OHCH), 3.83 To a solution of compound 12 or 14 (1 eq.) in anhydrous DMF
(s, 3H, OCH3), 3.89 (s, 3H, OCH3), 6.39 (d, J = 8.4 Hz, 1H, Ar– (0.25 M) NaH 60% dispersion in mineral oil (2.5 eq.) was
H), 6.74 (d, J = 8.4 Hz, 2H, Ar–H), 6.75 (d, J = 8.5 Hz, 1H, Ar–H), added at 0 °C. The mixture was stirred for almost 10 min after
7.05 (d, J = 8.4 Hz, 2H, Ar–H); 13C NMR (100 MHz, CDCl3): δ which benzyl bromide (1.2 eq.) and NaI (0.07 eq.) were added.
25.3, 29.4, 29.9, 31.1, 37.3, 39.2, 55.8, 60.9, 71.4, 103.3, 115.2, The reaction mixture was stirred at room temperature until
121.7 (q), 124.1, 129.5, 134.2 (q), 135.4 (q), 147.3 (q), 150.4 (q), complete benzylation of the starting material. The reaction
153.7 (q); anal. C 70.01, H 7.85%, calcd for C21H28O5, C 69.98, was quenched at 0 °C adding slowly a saturated aqueous solu-
H 7.83%.
tion of NH4Cl (25 mL mmol−1). The aqueous phase was
6-(7-(4-(Benzyloxy)phenyl)-5-hydroxyheptyl)-2,3-dimethoxy- extracted with EtOAc (3 × 30 mL mmol−1). The combined
phenol (13). To a cooled (0 °C) and vigorously stirred solution organic layers were washed with brine. The resulting organic
of 2-nitrobenzenesulfonylchloride (0.76 mmol, 0.170 g) and layers were dried over Na2SO4, filtered and concentrated under
alkene 10 (0.38 mmol, 0.17 g) in dry MeCN (2 mL) was slowly vacuum. The crude reaction mixture was purified by column
added (dropwise) hydrazine hydrate (1.53 mmol, 0.05 mL). The chromatography on silica gel to remove excess of DMF and
resulting suspension was allowed to slowly warm to room benzylbromide.
temperature, stirring vigorously for all night long. After 18 h of
2-(Benzyloxy)-1-(5-(benzyloxy)-7-(4-(benzyloxy)phenyl)heptyl)-
reaction, the crude was filtered and washed with EtOAc. The 3,4-dimethoxybenzene (15). The desired product was obtained
residue was dried over Na2SO4, filtered and dried under after 15 h of benzylation of 12 (2.22 mmol, 1.0 g) following the
vacuum. The crude was subsequently purified by using a short general procedure reported above. Purification by column
silica gel pad to obtain the desired compound 13 (0.162 g, chromatography (cyclohexane/EtOAc 8 : 2) furnished com-
95% yield). Rf = 0.4 (cyclohexane/EtOAc 6 : 4); 1H NMR pound 15 (1.05 g, 75%) as a transparent oil. Rf = 0.5 (cyclo-
(400 MHz, CDCl3): δ 1.65–1.33 (m, 8H, CH2), 2.60–2.44 (m, 3H, hexane/EtOAc 8 : 2); 1H NMR (400 MHz, CDCl3): δ 1.68–1.35
ArCH2CH2), 2.80–2.62 (m, 1H, ArCH2CH2), 3.67–3.57 (m, 1H, (m, 8H, CH2), 2.55–2.49 (m, 3H, ArCH2CH2), 2.70–2.62 (m, 1H,
OHCH), 3.84 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 5.05 (s, 2H, ArCH2CH2), 3.50–3.30 (m, 1H, OHCH), 3.86 (s, 3H, OCH3), 3.88
CH2–Bn), 6.41 (d, J = 8.4 Hz, 1H, Ar–H), 6.78 (d, J = 8.4 Hz, 2H, (s, 3H, OCH3), 4.47 (ABsystem, J = 6.0 Hz, Δν = 12 Hz, 2H, CH2-
Ar–H), 6.91 (d, J = 8.4 Hz, 2H, Ar–H), 7.12 (d, J = 8.4 Hz, 2H, Bn, aliphatic chain), 5.05 (s, 4H, CH2-Bn), 6.63 (d, J = 8.4 Hz,
Ar–H), 7.45–7.33 (m, 5H, Bn–H); 13C NMR (100 MHz, CDCl3): δ 1H, Ar–H), 6.82 (d, J = 8.4 Hz, 1H, Ar–H), 6.89 (d, J = 8.4 Hz,
25.3, 29.3, 29.9, 31.1, 37.4, 39.2, 54.8, 60.8, 70.0, 71.3, 103.3, 2H, Ar–H), 7.07 (d, J = 8.4 Hz, 2H, Ar–H), 7.45–7.33 (m, 15H,
114.8, 121.6 (q), 124.0, 127.5, 127.9, 128.6, 129.3, 134.6 (q), Bn–H); 13C NMR (100 MHz, CDCl3): δ 25.2, 29.7, 30.7, 31.0,
135.4 (q), 137.2 (q), 147.3 (q), 150.4 (q), 156.0 (q). Anal. 33.5, 35.9, 56.0, 60.9, 70.1, 70.7, 75.1, 78.3, 107.4, 114.7, 123.8,
C 74.66, H 7.64%, calcd for C28H34O5, C 74.64, H 7.61%.
127.4, 127.5, 127.8, 127.9, 127.9, 128.1, 128.3, 128.4, 128.5,
6-(7-(4-(Benzyloxy)-3-iodophenyl)-5-hydroxyheptyl)-2,3-dimetho- 129.0 (q), 129.3, 134.9 (q), 137.2 (q), 138.0 (q), 139.0 (q), 142.4
xyphenol (14). To a cooled (0 °C) and vigorously stirred solution (q), 150.7 (q), 151.9 (q), 156.9 (q); anal. C 79.99, H 7.36%, calcd
of 2-nitrobenzenesulfonylchloride (1.04 mmol, 0.231 g) and for C42H46O5, C 79.97, H 7.35%.
alkene 11 (0.52 mmol, 0.30 g) in dry MeCN (2.6 mL) was slowly
2-(Benzyloxy)-1-(5-(benzyloxy)-7-(4-(benzyloxy)-3-iodophenyl)
added (dropwise) hydrazine hydrate (2.08 mmol, 0.07 mL). The heptyl)-3,4-dimethoxybenzene (16). The desired product was
resulting suspension was allowed to slowly warm to room obtained after 15 h of benzylation of 14 (1.21 mmol, 0.70 g) fol-
temperature and to stir vigorously for all night long. After 18 h lowing the general procedure reported above. After purification
of reaction, the crude was filtered and washed with EtOAc. The by column chromatography on silica gel (cyclohexane/EtOAc
residue was dried on Na2SO4, filtered and concentrated in 8 : 2) compound 16 was obtained (0.65 g, 71%) as a transparent
vacuo. The crude was subsequently purified by using a short oil. Rf = 0.55 (cyclohexane/EtOAc 8 : 2); 1H NMR (400 MHz,
silica gel pad to obtain the desired compound 14 (0.27 g, 91% CDCl3): δ 1.55–1.39 (m, 6H, CH2), 1.81–1.74 (m, 2H, CH2),
yield). Rf = 0.45 (cyclohexane/EtOAc 6 : 4) 1H NMR (400 MHz, 2.55–2.48 (m, 3H, ArCH2CH2), 2.65–2.60 (m, 1H, ArCH2CH2),
CDCl3):
δ 1.82–1.30 (m, 8H, CH2), 2.65–2.51 (m, 3H, 3.40–3.34 (m, 1H, OHCH), 3.86 (s, 3H, OCH3), 3.89 (s, 3H,
ArCH2CH2), 2.78–2.65 (m, 1H, ArCH2CH2), 3.68–3.54 (m, 1H, OCH3), 4.46 (ABsystem, J = 12 Hz, Δν = 21 Hz, 2H, CH2–Bn, ali-
OHCH), 3.84 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 5.13 (s, 2H, phatic chain), 5.05 (s, 2H, CH2–Bn), 5.13 (s, 2H, CH2–Bn), 6.64
CH2–Bn), 5.87 (bs, 1H, OH phenolic), 6.41 (d, J = 8.5 Hz, 1H, (d, J = 8.4 Hz, 1H, Ar–H), 6.76 (d, J = 8.4 Hz, 1H, Ar–H), 6.83 (d,
Ar–H), 6.77 (d, Jortho = 8.5 Hz, 2H, Ar–H), 7.10 (dd, Jortho
=
J = 8.4 Hz, 2H, Ar–H), 7.02 (dd, Jortho = 8.4 Hz, Jmeta = 2.0 Hz,
8.3 Hz, Jmeta = 2.0 Hz, 1H, Ar–H), 7.32 (t, J = 7.3 Hz, 1H, Bn–H), 1H, Ar–H), 7.53–7.33 (m, 15H, Bn–H), 7.60 (d, Jmeta = 2.0 Hz,
7.40 (t, J = 7.4 Hz, 2H, Bn–H), 7.50 (d, J = 7.4 Hz, 2H, Bn–H), 1H, Ar–H);13C NMR (100 MHz, CDCl3): δ 25.1, 29.7, 30.3, 31.0,
7.65 (d, J = 2.0 Hz, 1H, Ar–H); 13C NMR (100 MHz, CDCl3): δ 33.5, 35.7, 56.1, 60.9, 70.8, 71.0, 75.1, 78.1, 86.8 (q), 107.4,
25.3, 29.4, 29.9, 30.6, 37.4, 39.0, 55.8, 60.9, 71.0, 71.1, 86.8 (q), 112.7, 123.8, 127.0, 127.5, 127.8, 127.8, 127.9, 128.1, 128.4,
103.3, 112.7, 121.6 (q), 124.0, 127.0, 127.8, 128.5, 129.3, 135.4 128.4, 128.5, 129.0 (q), 129.2, 136.7 (q), 137.2 (q), 138.1 (q),
(q), 136.7 (q), 136.9 (q), 139.3, 147.3 (q), 150.4 (q), 155.4 (q). 138.9 (q), 139.2 (q), 142.5 (q), 150.8 (q), 151.9 (q), 155.4 (q).
Anal. C 58.36, H 5.78%, calcd for C28H33IO5, C 58.34, H 5.77%. Anal. C 66.65, H 5.99%, calcd for C42H45IO5, C 66.66, H 5.99%.
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2-(Acetoxy)-1-(5-(acetoxy)-7-(4-(benzyloxy)phenyl)heptyl)-3,4-
2-(Benzyloxy)-1-(5-(benzyloxy)-7-(4-(benzyloxy)-3-iodophenyl)
dimethoxybenzene (17). To a solution of compound 13 heptyl)-5-bromo-3,4-dimethoxybenzene (19). Di-halogenated
(0.200 mmol, 0.090 g) in pyridine (0.5 mL) was added acetic product 19 was prepared by treating diarylheptanoid 16
anhydride (0.5 mL). The solution was stirred at room tempera- (1.41 mmol, 1.0 g) with NBS (1.69 mmol, 0.30 g) as reported in
ture until complete transformation of the starting material. the general procedure of bromination. After 18 h of reaction
After 2 h the reaction was quenched with water and the the mixture was quenched with water, extracted with EtOAc,
aqueous layer was extracted with EtOAc (3 × 10 mL mmol−1). dried and evaporated under vacuum and purified by using a
The resulting organic extracts were washed with a saturated silica gel pad to remove the succinimide and to give pure 19
aqueous solution of NaCl. The organic layers were collected, (1.06 g, 90% yield). Rf = 0.55 (cyclohexane/EtOAc 8 : 2) 1H NMR
dried on Na2SO4 and concentrated under reduced pressure to (400 MHz, CDCl3): δ 1.58–1.28 (m, 8H, CH2), 2.52 (t, J = 8.0 Hz,
afford the pure product 17 (0.104 g, quant). Rf = 0.7 (petroleum 2H, ArCH2), 2.56–2.50 (m, 1H, ArCH2CH2), 2.65–2.55 (m, 1H,
1
ether/EtOAc 7 : 3); H NMR (500 MHz, CDCl3): δ 1.32 (m, 2H, ArCH2CH2), 3.45–3.35 (m, 1H, OCH–Bn), 3.92 (s, 3H, OCH3),
CH2), 1.52 (m, 4H, CH2), 1.81 (m, 2H, CH2), 2.03 (s, 3H, 3.93 (s, 3H, OCH3), 4.46 (ABsystem, 2H, J = 12 Hz, Δν = 21 Hz,
CH3CO), 2.33 (s, 3H, CH3CO), 2.43 (m, 2H), 2.53 (m, 2H), 3.81 CH2–Bn, aliphatic chain), 5.04 (s, 2H, CH2–Bn), 5.14 (s, 2H,
(s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.91 (m, 1H, CHOAc), 5.03 CH2–Bn), 6.77 (d, J = 8.5 Hz, 1H, Ar–H), 7.05 (dd, J = 8.5 Hz, J =
(s, 2H, CH2Ph), 6.73 (d, J = 8.0 Hz, 1H, Ar–H), 6.85 (d, J = 2.1 Hz, 1H, Ar–H), 7.09 (s, 1H, Ar–H), 7.52–7.31 (m, 15H, Bn–
8.0 Hz, 1H, Ar–H), 6.88 (d, J = 8.5 Hz, 2H, Ar–H), 7.06 (d, J = H), 7.62 (d, J = 2.1 Hz, 1H, Ar–H). 13C NMR (100 MHz, CDCl3):
8.5 Hz, 2H, Ar–H), 7.29–7.43 (m, 5H, Bn–H); 13C NMR δ 25.1, 29.6, 30.2, 30.6, 33.4, 35.7, 61.0, 61.1, 70.8, 71.0, 75.2,
(125 MHz, CDCl3): δ 20.5, 21.2, 25.0, 29.6, 29.9, 30.9, 34.0, 77.9, 86.8 (q), 111.3 (q), 112.7, 125.9, 127.0, 127.3, 127.5, 127.8,
36.0, 56.1, 60.6, 70.1, 73.8, 110.1, 114.8, 123.6, 127.4, 127.5, 128.0, 128.1, 128.3, 128.5, 128.5, 129.2, 133.4 (q), 136.7 (q),
127.9, 128.5, 128.6, 129.2, 134.0, 137.2, 142.7, 151.6, 157.1, 137.1 (q), 137.5 (q), 139.2, 147.6 (q), 149.3 (q), 150.2 (q), 155.4
169.1, 170.9; anal. C 71.94, H 7.20%, calcd for C32H38O7, C, (q,). Anal. C 60.40, H 5.33%, calcd for C42H44BrIO5, C 60.37,
71.89; H, 7.16%.
H 5.31%.
General procedure for bromination of compounds 15 and 16
General procedure for iodination of compounds 15, 16, and 17
To a solution of starting aryl substrate 15 or 16 (1 eq.) in ACN To a solution of substrate 15, 16 or 17 (1 eq.) in ACN (0.25 M)
(0.25 M) and TFA (0.3 equiv.) was added NBS (1.1 eq.). The and TFA (0.3 eq.) was added NIS (1.1–5.0 eq.). The mixture was
mixture was stirred at room temperature and followed by TLC. stirred at room temperature and followed by TLC, GC-MS or
After disappearance of the starting material, the mixture was NMR. After disappearance of the starting material, the mixture
quenched with water. Extraction of aqueous layers was done was quenched with water. Extraction of aqueous layers was
with EtOAc (3 × 30 mL mmol−1) and the combined organic done with EtOAc (3 × 30 mL mmol−1) and the combined
layers were dried over Na2SO4 and filtered. Concentration of organic extracts were washed with a saturated aqueous solu-
the organic phase under reduced pressure gave the crude tion of Na2S2O3, dried over Na2SO4 and filtered. Concentration
product that was purified by silica gel chromatography.
of the organic phase under reduced pressure gave the crude
2-(Benzyloxy)-1-(5-(benzyloxy)-7-(4-(benzyloxy)-3-bromophenyl) product that was purified by silica gel chromatography or if
heptyl)-5-bromo-3,4-dimethoxybenzene (18). The desired pure used with any further purification.
product was obtained from bis-bromination of compound 15
2-(Benzyloxy)-1-(5-(benzyloxy)-7-(4-(benzyloxy)-3-iodophenyl)
(0.8 mmol, 0.5 g) with 2.2 eq. of NBS, following the general heptyl)-5-iodo-3,4-dimethoxybenzene (20). The di-iodinated
protocol of bromination reported above. After 18 h of reaction, product was prepared following the general procedure of iodi-
aqueous quenching, organic extraction and silica gel column nation described before, by treating diarylheptanoid 15 or 16
chromatography (cyclohexane/EtOAc 8 : 2) compound 18 was with different amounts of NIS. Diarylheptanoid 15 (1 eq.,
obtained (0.5 g, 99% yield) as a yellow-brown oil. Rf = 0.5 1.41 mmol, 1.0 g) was treated with 5 eq. of NIS (7.05 mmol,
(cyclohexane/EtOAc 8 : 2); 1H NMR (400 MHz, CDCl3): δ 1.59 g) to give 20 in 70% yield (0.98 mmol, 0.87 g). In this reac-
1.88–1.28 (m, 8H, CH2), 2.51 (t, J = 7.0 Hz, 2H, ArCH2), tion NIS was added portion-wise in 36 h. Diarylheptanoid 16
2.69–2.56 (m, 1H, ArCH2CH2), 2.75–2.69 (m, 1H, ArCH2CH2), (1 eq., 1.41 mmol, 1.0 g) treated with 1.2 equiv. of NIS
3.37–3.34 (m, 1H, OCH), 3.90 (s, 3H, OCH3), 3.91 (s, 3H, (1.69 mmol, 0.38 g) gave 20 after 18 h. The product 20 (1.24 g,
OCH3), 4.45 (ABsystem, J = 12 Hz, Δν = 21 Hz, 2H, CH2–Bn, ali- 99% yield) was obtained pure as a yellow oil after a silica gel
phatic chain), 5.01 (s, 2H, CH2–Bn), 5.13 (s, 2H, CH2–Bn), 6.83 pad purification to remove the succinimide. Rf = 0.55 (cyclo-
(d, J = 8.5 Hz, 2H, Ar–H), 6.96 (dd, J = 8.5 Hz, J = 2.1 Hz, 2H, hexane/EtOAc 8 : 2); 1H NMR (400 MHz, CDCl3): δ 1.84–1.26
Ar–H), 7.07 (s, 1H, Ar–H), 7.48–7.34 (m, 16H, 15Bn–H, 1Ar–H); (m, 8H, CH2), 2.48 (t, J = 8.0 Hz, 2H, ArCH2), 2.55–2.46 (m, 1H,
13C NMR (100 MHz, CDCl3): δ 25.1, 29.6, 30.4, 30.6, 33.4, 35.6, ArCH2CH2), 2.67–2.59 (m, 1H, ArCH2CH2), 3.95–3.33 (m, 1H,
61.0, 61.1, 70.8, 70.9, 75.2, 77.9, 111.3 (q), 112.3 (q), 113.9, OCH–Bn), 3.88 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.46
127.0, 127.3, 127.5, 127.8, 128.0, 128.1, 128.1, 128.4, 128.5, (ABsystem, J = 12 Hz, Δν = 21 Hz, 2H, CH2–Bn, aliphatic chain),
128.5, 133.1 (q), 133.4 (q), 136.5 (q), 136.7 (q), 137.5, 138.8, 5.02 (s, 2H, CH2–Bn), 5.13 (s, 2H, CH2–Bn), 6.76 (d, J = 8.5 Hz,
147.6 (q), 149.2 (q), 150.1 (q), 153.1 (q); anal. C 64.02, H 1H, Ar–H), 7.03 (dd, J = 8.5 Hz, J = 2.1 Hz, 1H, Ar–H), 7.51–7.29
5.66%, calcd for C42H44Br2O5, C 63.97, H 5.62%.
(m, 16H, 15Bn–H, 1Ar–H), 7.60 (d, J = 2.1 Hz, 1H, Ar–H); 13C
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NMR (100 MHz, CDCl3): δ 25.1, 29.6, 30.3, 30.7, 33.4, 35.7, being heated under argon at 80 °C for 24 h, the reaction
60.9, 61.0, 70.8, 71.0, 75.2, 77.9, 85.1 (q), 86.8 (q), 112.7, 127.0, mixture was allowed to cool at room temperature and then
127.5 (q), 127.6, 127.8, 127.8, 128.0, 128.1, 128.4, 128.4, 128.5, quenched with
a saturated aqueous solution of NH4Cl
128.5, 129.2, 133.1 (q), 136.7 (q), 137.1 (q), 137.5 (q), 139.2, (40 mL). The mixture was extracted with EtOAc (3 × 40 mL).
146.7 (q), 151.3 (q), 151.9 (q), 155.4 (q); anal. C 57.17, H The organic layers were separated, dried over Na2SO4, filtered
5.03%, calcd for C42H44I2O5, C 57.15, H 5.02%.
and concentrated under vacuum. The crude was purified on
2-(Acetoxy)-1-(5-(acetoxy)-7-(4-(benzyloxy)-3-iodophenyl)heptyl)- silica gel chromatography (pure petroleum ether to petroleum
5-iodo-3,4-dimethoxybenzene (21). Starting from 17 (0.85 mmol, ether/EtOAc 9.5 : 0.5). The recollected fractions (except for the
0.454 g) and portion-wise addition of NIS (4.4 eq.) after 4 d of individuated unreacted starting material and its dehaloge-
reaction and purification by silica gel column chromatography nated derivatives) were subjected to deacetylation with a cata-
(hexane/EtOAc 8 : 2) compound 21 (0.467 g 70%) was obtained lytic amount of Na in MeOH (2 mL) for 2 h at room tempera-
as a pale yellow solid. Rf = 0.6 (hexane/EtOAc 8 : 2); 1H NMR ture. The work-up of reaction was carried out on adding water
(400 MHz, CDCl3): δ 1.24 (m, 4H, CH2), 1.56 (m, 2H, CH2), 1.81 and extracting with EtOAc. The crude was subjected to catalytic
(m, 2H, CH2), 2.04 (s, 3H, CH3CO), 2.33 (s, 3H, CH3CO), 2.52 debenzylation by using Pd/C 10%, H2 and MeOH as the
(m, 4H), 3.80 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.95 (m, 1H, solvent. After purification on silica gel chromatography (pet-
CHOAc), 5.12 (s, 2H, CH2Ph), 6.76 (d, J = 8.4 Hz, 1H, Ar–H), roleum ether/EtOAc 7 : 3) myricanol was obtained (0.009 g,
7.07 (dd, J = 8.4 Hz, 2.0 Hz, 1H, Ar–H), 7.24 (s, 1H, Ar–H), 12% over 3 steps).
7.31–7.50 (m, 5H, Bn–H), 7.61 (t, J = 2.0 Hz, 1H, Ar–H); 13C
1H NMR (500 MHz, CDCl3): δ 1.52–1.62 (m, 3H), 1.66–1.76
NMR (100 MHz, CDCl3): δ 20.5, 21.2, 25.2, 28.9, 30.4, 33.9, (m, 2H), 1.88–2.00 (m, 3H), 2.28–2.41 (m, 1H), 2.50–2.62 (m,
34.9, 35.8, 56.2, 60.5, 70.9, 73.6, 86.8, 92.2, 112.6, 120.8, 123.6, 1H), 2.81 (dt, J = 18 Hz, J = 2.4 Hz, 1H), 2.85–2.94 (m, 2H), 3.88
126.4, 127.8, 128.5, 129.2, 128.6, 130.7, 136.2, 136.6, 139.1, (s, 3H), 4.01 (s, 3H), 4.06–4.16 (m, 1H), 5.82 (bs, 1H), 6.90 (d,
141.5, 141.9, 151.9, 155.5, 168.8, 170.8; anal. C 48.91, H 4.63%, J = 8.3 Hz, 1H), 6.91 (s, 1H), 7.10 (dd, J = 8.3 Hz, J = 2.2 Hz,
calcd for C32H36I2O7, C 48.87, H 4.61%.
1H), 7.19 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H).
2-(2-(Benzyloxy)-5-(3-(benzyloxy)-7-(2-(benzyloxy)-3,4-dimethoxy-
phenyl)heptyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(22).
A
flame-dried flask was charged with PdCl2dppf Conflicts of interest
(0.01 mmol, 0.01 g). Vacuum/argon cycle was again repeated in
the flask and a solution of starting iodide 16 (0.12 mmol,
0.09 g) in toluene (1 mL) was added. Pinacolborane
(0.20 mmol, 0.03 mL) and Et3N (0.13 mL) were added under
argon. The flask was sealed and heated to 110 °C for 20 h.
After cooling to rt, the reaction mixture was hydrolysed with
aqueous saturated NH4Cl (3 mL) and extracted with EtOAc (3 ×
5 mL). The crude was purified by column chromatography on
silica gel (cyclohexane/EtOAc 7 : 3) to eliminate the excess of
pinacolborane. A second purification was made (cyclohexane/
EtOAc 9 : 1) which afforded the right product as a deliquescent
white solid (66 mg, 60% yield). Rf = 0.3 (cyclohexane/EtOAc
9 : 1); 1H NMR (400 MHz, CDCl3): δ 1.87–1.28 (m, 8H, CH2),
1.38 (s, 12H, CH3-pinacol), 2.56 (t, J = 8.0 Hz, 2H, ArCH2),
2.71–2.52 (m, 2H, ArCH2CH2), 3.48–3.36 (m, 1H, OCH–Bn),
3.86 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.49 (s, 2H, CH2–Bn, ali-
phatic chain), 5.06 (s, 2H, CH2–Bn), 5.11 (s, 2H, CH2–Bn), 6.64
(d, J = 8.5 Hz, 1H, Ar–H), 6.84 (d, J = 8.5 Hz, 1H, Ar–H), 6.87 (d,
J = 8.5 Hz, 1H, Ar–H), 7.60–7.29 (m, 16H, 15Bn–H, 1Ar–H); 13C
NMR (100 MHz, CDCl3): δ 25.0, 25.2, 29.7, 30.8, 31.1, 33.6,
36.0, 56.1, 60.9, 70.2, 70.8, 75.2, 78.4, 83.5 (q), 107.4, 112.3,
123.8, 126.8, 127.2, 127.4, 127.8, 127.8, 128.0, 128.1, 128.3,
128.4, 128.9, 132.3, 134.4 (q), 136.5, 137.8 (q), 138.0 (q), 139.0
(q), 142.4 (q), 150.7 (q), 151.8 (q), 161.6 (q); 11B NMR
(128 MHz, CDCl3) δ 31.34; anal. C 76.20, H 7.60%, calcd for
C48H57BO7, C 76.18, H 7.59%.
There are no conflicts to declare.
Acknowledgements
We thank the CNRS (Centre National de la Recherche
Scientifique), the “Ministere de l’Education Nationale et de la
Recherche”, France and the “Ministero dell’istruzione,
dell’università e della ricerca” Italy for financial support. A. B.
is very grateful to the “Ministero dell’istruzione, dell’università
e della ricerca” Italy, for a doctoral grant.
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