A strategy for the synthesis of the fargenone/fargenin family of natural products: Synthesis of the tricyclic core

Article abstract of DOI:10.1039/c2ob25489a

A synthesis of the core ring structure of the fargenin/fargenone family of natural products is presented. The general strategy is based upon biosynthetic speculation and exploits a cascade reaction, which transforms a spirocyclic dienone into the core ring system via a deprotonation-oxy-Michael-Wittig olefination sequence. This study represents the first synthesis work towards this family of natural products.

Full text of DOI:10.1039/c2ob25489a

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PAPER
A strategy for the synthesis of the fargenone/fargenin family of natural
products: synthesis of the tricyclic core†
Ross M. Denton* and James T. Scragg
Received 6th March 2012, Accepted 30th May 2012
DOI: 10.1039/c2ob25489a
A synthesis of the core ring structure of the fargenin/fargenone family of natural products is presented.
The general strategy is based upon biosynthetic speculation and exploits a cascade reaction, which
transforms a spirocyclic dienone into the core ring system via a deprotonation–oxy-Michael–Wittig
olefination sequence. This study represents the first synthesis work towards this family of natural
products.
1
1
and chavicol-(10). A series of divergent cyclisation reactions
of common intermediate 11 then affords the natural products
1
Introduction
The genus Illicium is characterized by a large number of biologi-
cally active and structurally interesting natural products and, in
particular, a range of oligomeric phenol-derived compounds,
which are linked through the aromatic ring (Fig. 1). Isolated in
–4.
There are two possible oxy-Michael cyclisations of 11, both
of which establish the characteristic [4.3.0] ring system found in
the fargenone/fargenin family. The first cyclisation, involving the
more substituted olefin of the bis enone, results in intermediate
2, from which either fargenin-(3) or the cage-like natural
product fargenone B-(1) are expected to arise via the indicated
transformations. The second possible oxy-Michael cyclisation of
1 gives rise to 4, an unnamed natural product which, after a
final oxy-Michael cyclisation and benzylic oxidation, is con-
verted into fargenone A-(2). This biogenetic speculation, which
implicates chavicol-(10) as the precursor to this family of sesqui
neolignans (and also to the simpler bi-aryls honokiol-(7) and
magnolol-(6)), has been corroborated in vitro by Brown and Sy
who have demonstrated that a variety of natural products includ-
ing dunnianol-(9), magnolol-(6) and compound 5, can be
obtained in low yield by treatment of chavicol-(10) with iron
1
2
007 from the methanol extract of the pericarps (fruit wall) of
Illicium fargesii are three such sesqui neolignans (fargenones
A-(2), B-(1) and fargenin-(3), Fig. 1). These structures, in
common with the un-named natural product 4, can be traced
back to the naturally occurring phenol chavicol-(10) (Fig. 1),
1
2
3
1
itself isolated numerous times from biologically active plant
4
extracts. While the isolation study of Fukuyama revealed that
structures 1 to 3 were not particularly effective in promoting
neurite outgrowth at the micromolar level in vitro, a number of
structurally related phenolic natural products, particularly those
isolated from Magnolia, have exhibited this type of biological
activity and have been the subject of recent total syntheses. For
example, we recently reported concise syntheses of honokiol-
5
6
7
12
(
7), 4′-O-methyl honokiol-(8) and dunnianol-(9). The syn-
trichloride.
thesis of honokiol-(7) and 4′-O-methyl honokiol-(8) has also
been accomplished by a number of other research groups as has
Our synthesis plan for this structurally interesting family of
natural products is based on the above analysis and, specifically,
on the use of intermediate 11 (or a protected equivalent thereof)
as a precursor from which the fargenones and fargenin should be
available via the pathways indicated in Scheme 1. Given that no
previous synthesis work has been reported on this group of
natural products we began our studies by targeting compound 5,
which represents the tricyclic core ring system of this family of
natural products. Specifically, we wished to ascertain the feasi-
bility of an approach in which the spirocyclic dienone 14 could
be transformed into the characteristic [4.3.0] ring system via a
8
9
the synthesis of a variety of analogues and related natural
10
products.
The relationship between structures 1 to 4 and chavicol-(10),
which has also been noted by Fukuyama, is depicted in
Scheme 1. This analysis reveals that the skeletally distinct tri-
meric natural products 1–4 are all very likely derived from
dienone 11, which is itself the product of an ortho/para-oxi-
dative phenolic coupling between simple phenols magnolol-(6)
2
13
cascade sequence involving deprotonation, oxy-Michael cycli-
sation and Wittig olefination (vide infra). This approach is
depicted in retrosynthetic form in Scheme 2.
School of Chemistry, University of Nottingham, University Park,
Nottingham, NG7 2RD, UK. E-mail: ross.denton@nottingham.ac.uk;
Fax: +44 (0)1159 514194; Tel: +44 (0)1159 513564
14
Recent work by Magnus et al., indicated that the desired
spirocyclisation of 15 to obtain intermediate 14 was likely to be
†
1
Electronic supplementary information (ESI) available. See DOI:
0.1039/c2ob25489a
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Fig. 1 Neolignan natural products isolated from Illicium and Magnolia plants and their likely biosynthetic precursor, chavicol-(10).
Scheme 1 Biogenetic speculation on the origin of the fargenin/fargenone natural products from chavicol-(10).
viable following bromo-acetalisation of 16. This biaryl was
directed ortho lithiation of commercial 4-allyl anisole followed
by quenching with freshly distilled trimethylborate afforded 18
in 75% isolated yield after hydrolysis of the derived arylboronate
ester with aqueous hydrochloric acid.
expected to arise, after protecting group manipulation, from the
Suzuki-Miyaura cross-coupling of 17 and 18. We were aware of
the potential difficulties in carrying the allyl group within 18
through a sequence of reactions in which isomerisation may
occur. However, this was deemed preferable to alternatives that
would involve progressing, for example, a protected alcohol, that
would have to be unmasked, oxidized and methylenated at a
later stage adding several steps to the sequence.
Suzuki-Miyaura cross-coupling of the latter compound with
bromophenol 17 afforded biaryl 20 in an excellent 94% yield
without isomerisation of the sensitive allyl group. Protection of
the hydroxyl group as a TBDMS ether was then carried out
under standard conditions. Subsequent demethylation with
BCl ·SMe then afforded 16 in excellent yield leaving the silyl
3
2
group intact. Conversion of this intermediate compound to
mixed acetal 15 was next achieved using bromine and ethyl
vinyl ether.
Results and discussion
14
Our studies (Scheme 3) began with the preparation of the
With acetal 15 in hand the first of the key steps in the
sequence towards model compound 5 could be attempted
(Scheme 4). Using conditions developed by Magnus et al. we
boronic acid coupling partner 18, which was available from our
7
5
14
previous syntheses of dunnianol-(9) and honokiol-(7). Thus,
5630 | Org. Biomol. Chem., 2012, 10, 5629–5635
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Scheme 4 Reagents and conditions. (a) CsF, Na
.5 h, 99%; (b) 2 M HCl, dioxane, reflux, 2 h, 94%.
2
SO
4
, DMF, 130 °C,
1
Scheme 2 Retrosynthetic analysis of tricyclic core structure 5.
problematic and, therefore, the crude material was progressed
directly to the pivotal cascade reaction. We hoped that this
process would deliver 5, the characteristic tricyclic ring system
of the fargenin/fargenone family of natural products from spiro-
cycle 14 (Scheme 5). Specifically, we reasoned that, upon treat-
ment with excess ylide 25, the spirocyclic lactol would undergo
a sequence of reactions beginning with deprotonation and ring
opening to afford 26. This represents a truncated and activated
version of key intermediate 11 (Scheme 1), which is expected
15
to undergo rapid oxy-Michael cyclisation to afford tricyclic
enolate 27. Finally, methylenation of the aldehyde within
2
7 should afford the target model compound 5 upon acidic
work up.
Unfortunately, despite numerous attempts, we were unable to
control the cascade sequence to deliver compound 5 cleanly in
an acceptable yield. We summarise below (Table 1) the results of
some of our experiments (Scheme 6).
An initial reaction (entry 1) involving exposure of 14 to 3
equivalents of ylide 25 at room temperature afforded a complex
Scheme 3 Reagents and conditions. (a) (i) s-BuLi, TMEDA, THF,
−
78 °C to rt, 1 h, (ii) B(OMe)
Pd (dba) 10 mol%, S-Phos (30 mol%), KF, THF–H
5 h, 94%; (c) TBDMSCl, imidazole, DMF, 1 h, 99%; (d) BCl
3
, 24 h, (iii) aq. HCl, 1 h, 75%; (b)
1
13
mixture of products. Inspection of H and C NMR spectra and
comparison with the NMR data reported for 5 by Brown and Sy
indicated that the desired compound was present in small
amounts since peaks at δ 6.51, 4.70, 3.00 and 2.75, correspond-
ing to protons 2′a, 2′b, 3′ and 5′ respectively, were visible.
2
3
2
O (10 : 1), reflux,
1
1
0
3
·SMe
NEt, CH Cl
2
,
,
,2-DCE, reflux, 18 h, 89%; (e) Br
2
, CH
2
CHOEt, i-Pr
2
2
2
°C, 12 h, 92%.
Based on this we made several attempts to improve upon this
reaction and, given that we observed a substantial amount of
starting material, we conducted further experiments at 50 °C. At
this temperature (entry 2) we obtained a much simpler reaction
mixture from which we were able to isolate a tricyclic compound
heated 15 to 130 °C in DMF in the presence of CsF and we were
pleased to observe, firstly, cleavage of the silyl ether followed by
a dearomatising spirocyclization, that afforded dienone 22 in
excellent yield; hydrolysis of the acetal within 22 was then
examined. This was best achieved by refluxing with aqueous
HCl, which afforded a 94% yield of crude material. Inspection
1
whose H NMR data was similar to that of the desired product 5
in 55% yield. Closer inspection revealed that the material con-
tained an additional alkene and the spectroscopic data were con-
sistent with structure 29. The stereochemistry of the ring
junction was confirmed via a NOESY experiment (see Fig. 2) in
which the expected interactions between protons on the convex
face of the molecule were observed.
1
13
of H and C NMR spectra revealed that the crude product was
a mixture in which lactol 14 was a major constituent. We believe
that small amounts of aldehyde 24 were also present as a minor
component in the complex mixture. This is supported by the
1
presence of a triplet at δ 9.90, J = 1.0 Hz. Also present in the H
NMR were peaks at δ 4.72, 2.98 and 2.72, indicative of protons
located at positions 3′, 2′a and 2′b respectively, in 5 as character-
ised by Brown and Sy. Purification of this mixture by flash
Having obtained compound 29, which contains the desired
[4.3.0] ring system, in reasonable yield we sought to adjust the
reaction conditions to prevent the unwanted second Wittig
methylenation from occurring. To this end we adjusted the ratio
1
2
chromatography using normal phase silica gel proved to be
This journal is © The Royal Society of Chemistry 2012
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Scheme 5 Proposed cascade reaction to access the tricyclic core model system from lactol 14.
Table 1 Conditions screened to construct the tricyclic core
Entry
Ylide source
Base
Solvent
Temp.
Time
Product (yield)
1
2
3
4
Ph
Ph
Ph
—
3
PMeBr (3.0 eq.)
3
PMeBr (3.5 eq.)
3
PMeBr (1.1 eq.)
KHMDS (2.5 eq.)
KHMDS (3.0 eq.)
KHMDS (2.7 eq.)
t-BuOK (2.5 eq.)
THF
THF
THF
THF
r.t.
1.5 h
1.5 h
1.5 h
1 h
n/a
50 °C
50 °C
50 °C
29 (55%)
30 (48%)
30 (37%)
Scheme 6 Result of the cascade reaction on lactol 14.
Fig. 2 Key NOESY interactions for compound 29.
of phosphonium salt to base (entry 3). Frustratingly, this resulted
in the formation of yet another unwanted product, this time a
simple biaryl 30, which we had also isolated and characterised
Conclusion
5
before as a by-product during our synthesis of honokiol.
This by-product was also obtained when the starting material
was heated with other bases including potassium tert-butoxide
Model compound 29, which contains the characteristic [4.3.0]
ring system of the fargenin/fargenone family of natural products,
was prepared from 14 using a cascade sequence in which acti-
vated dienone 26 was an intermediate. This provides the first
entry to this class of natural products, validates our synthesis
strategy and corroborates the oxy-Michael cyclisation proposed
for intermediate 11 in Scheme 1. A modified version of this
(entry 4). Additional experiments in which the ratio of phos-
phonium salt to base were further varied resulted in very
complex mixtures of products in which varying amounts of
products 29 and 30 were visible, however, none were as clean as
entry 2.
5632 | Org. Biomol. Chem., 2012, 10, 5629–5635
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strategy that avoids the Wittig problem is now underway in our
laboratory.
0.735 mmol) dropwise and the solution was stirred for 15 min
before i-Pr NEt (0.205 mL, 1.18 mmol) was added. A solution
2
of 16 (100 mg, 0.294 mmol) in CH Cl (10.0 mL) was added
2
2
dropwise and the solution was stirred for 12 h. The solution was
warmed to rt, diluted with CH Cl (10.0 mL), washed with sat.
Experimental
2
2
aq. NaHCO (2 × 10.0 mL), washed with brine (2 × 10.0 mL),
3
NMR spectra were recorded on a Bruker DPX400 instrument as
dilute solutions in the indicated deuterated solvent. All chemical
shifts (δ) are reported in parts per million (ppm) relative to
residual solvent peaks. All chemical shifts are reported relative
dried over Na SO4 and concentrated under reduced pressure.
2
Purification by flash chromatography (petroleum ether–EtOAc,
9
: 1) gave 15 (133 mg, 92%) as a colourless oil, R 0.68
f
(
(
petroleum ether–EtOAc, 9 : 1).
to CHCl (δH = 7.27 ppm and δC = 77.0 ppm). Mass spectra
3
1
H NMR (400 MHz, CDCl ): δ 7.40 (d, J = 8.7 Hz, 2H), 7.16
3
were recorded on either VG Micromass 70E, VG Autospec or
Micromass LCTOF instruments. Infrared spectra were recorded
on a Pelkin-Elmer 1600 FTIR instrument as a dilute solution in
the indicated solvent. Reactions were monitored using TLC on
Polygram® SIL G/UV254 0.25 mm silica gel pre-coated glass
sheets with fluorescent indicator. Flash chromatography was per-
formed using Fluorochem silica gel 60, 35–70 micron. The sol-
vents used were purified according to standard literature
techniques and stored under argon.
s, 1H), 7.10–7.08 (m, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.99 (ddt,
J = 16.9, 10.0 and 6.8 Hz, 1H), 5.14–5.06 (m, 3H), 3.62 (dq, J =
.0 and 7.0 Hz, 1H), 3.46 (dq, J = 7.0 and 7.0 Hz, 1H), 3.39
dd, J = 6.8 Hz, 2H), 3.37–3.31 (m, 2H), 1.12 (t, J = 7.0 Hz,
7
(
3
13
H), 1.01 (s, 9H), 0.23 (s, 6H); C NMR (100 MHz, CDCl3):
δ 155.0, 151.8, 137.5, 135.1, 133.1, 131.3, 131.2, 130.8, 128.2,
19.7, 118.8, 116.0, 102.6, 63.0, 39.6, 31.7, 25.8, 18.3, 15.1,
4.2; IR (CHCl ) 3082, 3011, 2980, 2958, 2932, 2898, 2859,
1
−
3
−1
1
639, 1607, 1514, 1488, 1472, 1256, 1102, 993, 909 cm .
+
+
HRMS (ESI ) cald. for C H O NBrSi (M + NH ) requires
25
39
3
4
6
-Allyl-2-hydroxyspiro[chroman-4,1′-cyclohexa[2,5]dien]-4′-one
508.1877; found 508.1875.
(14)
To a solution of HCl (2.00 mL of a 2.00 M aqueous solution)
and dioxane (2.00 mL) was added 22 (50.0 mg, 0.170 mmol)
and the solution was stirred at rt for 1 h before being heated to
5
-Allyl-4′-(tert-butyldimethylsilyloxy)biphenyl-2-ol (16)
To a solution of 21 (310 mg, 0.874 mmol) in 1,2-DCE
(5.00 mL) was added BCl ·SMe (0.437 mL, 1.75 mmol of a
reflux for 2 h. The solution was cooled to rt, diluted with H O
3 2
2
2
.00 M solution in CH Cl ) and the solution was heated to
2 2
(10.0 mL), extracted with EtOAc (3 × 10.0 mL), washed with
reflux for 18 h. The solution was cooled to rt, H O (5.00 mL)
was added and the solution was stirred for 15 min. The solution
was diluted with CH Cl (20.0 mL), washed with brine (3 ×
2
brine (3 × 10.0 mL), dried over MgSO and concentrated under
2
4
reduced pressure to give 14 (43.0 mg, 94%) as a colourless oil,
R 0.34 (petroleum ether–EtOAc, 2 : 1).
2
2
f
1
0.0 mL), dried over MgSO and concentrated under reduced
4
H NMR: (400 MHz, CDCl ) δ 9.90 (t, J = 1.0 Hz, 1H),
3
pressure. Purification by flash chromatography (petroleum ether–
EtOAc, 9 : 1) gave 16 (265 mg, 89%) as a colourless oil, R 0.49
7
6
.45–7.39 (m, 2H), 7.18 (d, J = 1.3 Hz, 1H), 7.07–6.99 (m, 4H),
.91 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 9.9 and 3.5 Hz, 2H), 6.76
f
(
petroleum ether–EtOAc, 9 : 1).
(d, J = 2.0 Hz, 1H), 6.37 (dd, J = 10.0 and 1.9 Hz, 1H), 6.39
(dd, J = 10.0 and 1.9 Hz, 1H), 6.01–5.83 (m, 3H), 5.78–5.73
(m, 2H), 5.12–5.00 (m, 5H), 4.73–4.71 (m, 1H), 4.43–4.42 (m,
1
H NMR (400 MHz, CDCl ): δ 7.33 (d, J = 8.7 Hz, 2H), 7.06
3
(dd, J = 8.0 and 1.7 Hz, 1H), 7.04 (d, J = 1.7 Hz, 1H), 6.95 (d,
J = 8.7 Hz, 2H), 6.91 (d, J = 8.0 Hz, 1H), 5.98 (ddt, J = 16.8,
0.1 and 6.5 Hz, 1H), 5.10 (dd, J = 16.8 and 1.6 Hz, 1H), 5.08
s, 1H), 5.06 (dd, J = 10.1 and 1.6 Hz, 1H), 3.36 (d, J = 6.5 Hz,
1
2
H), 3.36 (t, J = 5.4 Hz, 3H), 3.25 (d, J = 6.1 Hz, 2H),
.98–2.92 (m, 2H), 2.77–2.65 (m, 3H), 2.42–2.14 (m, 5H), 1.88
1
(
(dd, J = 6.5 and 1.4 Hz, 1H), 1.83 (dd, J = 6.5 and 1.4 Hz, dd),
13
13
2
H), 1.02 (s, 9H), 0.25 (s, 6H); C NMR (100 MHz, CDCl3):
1.79 (s, 1H); C NMR (100 MHz, CD3CN): δ 207.0, 199.6,
196.3, 158.7, 158.6, 155.4, 155.12, 154.8, 152.7, 151.3, 148.0,
139.3, 138.9, 134.5, 134.0, 133.8, 132.9, 131.5, 131.4, 131.2,
130.5, 130.2, 130.0, 129.5, 129.3, 129.1, 129.0, 128.8, 128.1,
127.3, 125.7, 124.5, 120.5, 119.4, 119.2, 117.2, 116.9, 115.9,
δ 155.6, 150.9, 137.9, 132.3, 130.3, 130.3, 129.9, 128.9, 127.8,
1
20.9, 115.6, 115.6, 39.5, 25.8, 18.3, −4.3; IR (CHCl ) 3553,
3
3
011, 2958, 2932, 2898, 2859, 1606, 1514, 1491, 1264, 1170,
1
−
−
9
10 cm− . HRMS: (ESI ) cald. for C H O Si (M − H)
21 27
2
requires 339.1786; found 339.1782.
115.8, 115.6, 115.4, 115.3, 115.2, 110.5, 110.3, 101.3, 98.7,
9
4
3
1
8.2, 91.6, 91.4, 88.8, 88.6, 88.5, 84.2, 81.6, 73.7, 71.1, 46.9,
6.4, 45.7, 45.2, 43.9, 42.2, 40.8, 40.6, 40.2, 39.9, 39.8, 39.6,
5
-Allyl-2-methoxyphenylboronic acid (18)
8.0, 36.6; IR (CHCl ) 3674, 3584, 3081, 3011, 2980, 2932,
3
721, 1666, 1638, 1626, 1611, 1515, 1493, 1434, 1402, 1244,
To a solution of 19 (2.08 mL, 13.5 mmol) in THF (50 mL) at
−1
+
1179, 1131, 1043, 982 cm . HRMS (ESI ) cald. for
−
78 °C was added TMEDA (2.02 mL, 13.5 mmol) and s-BuLi
+
C H O Na (M + Na) requires 291.0992; found 291.0992.
1
7 16 3
(
14.6 mL, 20.2 mmol of a 1.39 M solution in hexanes) dropwise
over 15 min and the solution was stirred for 1 h. The reaction
mixture was then warmed to room temperature and stirred for 1 h
(
(
5′-Allyl-2′-(2-bromo-1-ethoxyethoxy)biphenyl-4-yloxy)-
tert-butyl)dimethylsilane (15)
before B(OMe) (1.39 mL, 13.5 mmol) was added and the reac-
3
tion was stirred for a further 24 h. The reaction was acidified
(1 M HCl to pH 3) and stirred for an additional 1 h. The reaction
was diluted with EtOAc (50 mL), washed with brine (3 ×
To a solution of Br2 (30.1 μL, 0.587 mmol) in CH Cl2
(
2
10.0 mL) at 0 °C was added ethyl vinyl ether (70.4 μL,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5629–5635 | 5633

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−
1
5
0 mL), dried over MgSO and concentrated in vacuo. Purifi-
1494, 1472, 1464, 1363, 1173, 1146, 1070, 1044, 913 cm .
4
+
+
cation by flash chromatography (petrol–Et O, 3 : 1) gave 18
HRMS (ESI ) cald. for C H O Si (M + H) requires
22 30 2
2
(
(
1.94 g, 75%) as a colourless solid, mp = 77–79 °C, R = 0.13
377.1902; found 377.1907.
f
petrol–Et O, 3 : 1).
2
1
H NMR: (400 MHz, CDCl ) δ 7.67 (d, J = 2.4 Hz, 1H), 7.27
3
6
-Allyl-2-ethoxyspiro[chroman-4,1′-cyclohexa[2,5]dien]-4′-one
(dd, J = 8.5 and 2.4 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.05 (br
(
22)
s, 2H), 5.97 (ddt, J = 16.8, 10.1 and 6.7, 1H), 5.07 (dd, J = 16.8
and 1.5 Hz, 1H), 5.09 (dd, J = 10.1 and 1.5 Hz, 1H), 3.91 (s,
3
δ 163.1, 137.7, 136.9, 132.9, 132.6, 132.6, 115.6, 110.1, 55.6,
3
1
To a flame dried mixture of CsF (46.5 mg, 0.306 mmol) and
1
3
H), 3.37 (d, J = 6.7 Hz, 2H); C NMR: (100 MHz, CDCl3)
Na SO4 (145 mg, 1.02 mmol) was added 15 (50.0 mg,
2
0
1
.102 mmol) in DMF (10.0 mL) and the solution was heated to
30 °C for 1.5 h. The solution was cooled to rt, diluted with
9.3; IR: (neat) 3422, 3196, 2958, 1633, 1606, 1511, 1410,
−1
+
339, 1098, 966, 816 cm . HRMS (EI ) cald. for C H O B
1
0 13 3
+
Et O (20.0 mL), washed with H O (3 × 20.0 mL), dried over
2 2
(M) requires 192.0958, found 192.0960.
MgSO and concentrated under reduced pressure. Purification by
4
flash chromatography (petroleum ether–EtOAc, 7 : 3) gave 22
(
30.1 mg, 99%) as a colourless oil, R 0.37 (petroleum ether–
f
5
′-Allyl-2′-methoxybiphenol-4-ol (20)
EtOAc, 7 : 3).
1
To a solution of 17 (199 mg, 1.15 mmol) in THF (10 mL) and
H NMR: (400 MHz, CDCl ) δ 7.46 (dd, J = 10.0 and 3.2 Hz,
3
H O (1 mL) was added 18 (330 mg, 1.72 mmol), KF (300 mg,
1H), 7.04 (dd, J = 8.4 and 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H),
6.81 (dd, J = 10.0 and 3.2 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H),
6.37 (dd, J = 10.0 and 1.8 Hz, 1H), 6.23 (dd, J = 10.0 and 1.8
Hz, 1H), 5.93–5.83 (m, 1H), 5.38 (dd, J = 3.0 and 3.0 Hz, 1H),
5.05–5.00 (m, 2H), 3.93 (dq, J = 7.2 and 3.0 Hz, 1H), 3.65 (dq,
J = 7.2 and 3.0 Hz, 1H), 3.25 (d, J = 6.4 Hz, 2H), 2.27 (dd, J =
14.0 and 3.0 Hz, 1H), 2.13 (dd, J = 14.0 and 3.0 Hz, 1H, 1.23 (t,
2
5
.75 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
(
142 mg, 0.345 mmol) and Pd (dba) (66.1 mg, 0.115 mmol)
2
3
and the solution was heated to reflux and stirred for 15 h. The
reaction was cooled to room temperature, diluted with EtOAc
(25 mL) and washed with 1 M HCl (2 × 25 mL) and brine (2 ×
2
5 mL), dried over MgSO and concentrated in vacuo. Purifi-
4
13
cation by flash chromatography (petrol–EtOAc, 3 : 1) gave 20
J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl ): δ 186.1, 154.9,
3
(
259 mg, 94%) as a yellow oil, R 0.48 (petrol–EtOAc, 3 : 1).
154.2, 148.4, 137.3, 133.5, 129.7, 128.6, 128.4, 126.1, 119.3,
118.5, 115.9, 95.6, 64.4, 40.7, 39.3, 36.4, 15.2; IR (CHCl3)
3081, 3011, 2981, 2933, 1731, 1665, 1625, 1515, 1495, 1434,
1402, 1374, 1345, 1259, 1178, 1131, 1119, 1066, 1043,
f
1
H NMR: (400 MHz, CDCl ) δ 7.43 (d, J = 8.8 Hz, 2H), 7.13
3
(
(
5
s, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.88
d, J = 8.8 Hz, 2H), 5.99 (ddt, J = 17.0, 11.5 and 6.7 Hz, 1H),
.11 (dd, J = 17.0 and 1.9 Hz, 1H), 5.07 (dd, J = 11.5 and 1.9
990 cm− . HRMS (ESI ) cald. for C H O Na (M + Na)
1
+
+
19 20 3
Hz, 1H), 4.80 (br s, 1H), 3.80 (s, 3H), 3.38 (d, J = 6.7 Hz, 2H);
requires 319.1305; found 319.1294.
1
3
C NMR: (100 MHz, CDCl ) δ 154.9, 154.5, 137.8, 132.3,
3
1
3
1
31.2, 131.0, 130.8, 130.2, 128.1, 115.6, 114.9, 111.3, 55.7,
8
,8b-Diallyl-3-methylene-3,4,4a,9b-tetrahydrodibenzo[b,d]furan
9.4; IR: (CHCl ) 3596, 3082, 3009, 2935, 2837, 1731, 1639,
3
−1
(
29)
613, 1591, 1518, 1496, 1256, 1174, 1044, 1029, 835 cm
.
+
+
HRMS: (ESI ) cald. for C H O Na (M + N) requires
2
1
6 16 2
To a solution of Ph PMeBr (91.8 mg, 0.258 mmol) in THF
3
63.1039, found 263.1043.
(
0
2.50 mL) was added KHMDS (0.448 mL, 0.224 mmol of a
.500 M solution in toluene) dropwise over 15 min and the solu-
tion was stirred for 30 min before a solution of 14 (20.0 mg,
4.6 μmol) in THF (2.50 mL) was added dropwise over 15 min
(
(
5′-Allyl-2′-methoxybiphenyl-4-yloxy)(tert-butyl) dimethylsilane
21)
7
and the solution was heated to 50 °C for 1.5 h. The solution was
cooled to rt, diluted with EtOAc (20.0 mL), washed with brine
(3 × 20.0 mL), dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography gave 29
To a solution of 20 (363 mg, 1.78 mmol) in DMF (10.0 mL)
was added imidazole (424 mg, 6.23 mmol) and TBDMSCl
(402 mg, 2.65 mmol) and the solution was stirred for 1 h. The
solution was diluted with Et O (20.0 mL), washed with H O
(10.9 mg, 55%) as a colourless oil, R 0.76 (petroleum ether–
2
2
f
(
3 × 20.0 mL), dried over MgSO4 and concentrated under
reduced pressure. Purification by flash chromatography
petroleum ether–EtOAc, 9 : 1) gave 21 (630 mg, 99%) as a
EtOAc, 3 : 1).
1
H NMR (400 MHz, CDCl ): δ 6.95 (s, 1H), 6.93 (d, J = 8.5
3
(
Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.22 (d, J = 9.9 Hz, 1H), 5.95
(ddt, J = 16.8, 10.0 and 6.8 Hz, 1H), 5.83–5.73 (m, 1H), 5.52
(d, J = 9.9 Hz, 1H), 5.15–5.04 (m, 4H), 4.97 (d, J = 11.8 Hz,
2H), 4.70 (t, J = 3.7 and 3.7 Hz, 1H), 3.33, (d, J = 6.8 Hz, 2H),
2.87 (dd, J = 15.9 and 3.8 Hz, 1H), 2.70–2.63 (m, 2H), 2.23
(dd, J = 14.1 and 7.6 Hz, 1H). C NMR (100 MHz, CDCl3):
δ 157.0, 138.1, 137.6, 133.8, 133.7, 132.6, 131.5, 128.6, 128.1,
123.1, 118.4, 115.5, 114.4, 110.0, 85.3, 48.2, 42.4, 39.9, 39.1;
colourless oil, R 0.71 (petroleum ether–EtOAc, 9 : 1).
f
1
H NMR (400 MHz, CDCl ): δ 7.42 (d, J = 8.6 Hz, 2H), 7.15
3
(
d, J = 2.0 Hz, 1H), 7.12 (dd, J = 8.4 and 2.0 Hz, 1H), 6.92 (d,
J = 8.4 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.01 (ddt, J = 17.0,
0.2, and 6.4 Hz, 1H), 5.11 (dd, J = 17.0 and 1.6 Hz, 1H), 5.07
dd, J = 10.2 and 1.6 Hz, 1H), 3.80 (s, 3H), 3.39 (d, J = 6.4 Hz,
13
1
(
2
1
3
H), 1.03 (s, 9H), 0.26 (s, 6H); C NMR (100 MHz, CDCl3):
δ 155.0, 154.8, 137.9, 132.3, 131.4, 131.1, 130.6, 130.4, 128.0,
19.5, 115.6, 111.5, 55.8, 39.5, 25.8, 18.3, −4.3; IR (CHCl3)
080, 3011, 2958, 2932, 2899, 2859, 1638, 1607, 1586, 1515,
IR (CHCl ) 2960, 2929, 2872, 1731, 1593, 1463, 1438, 1379,
3
−1
+
1
3
1296, 1265, 1177, 1122, 1071, 909 cm . HRMS (ESI ) cald.
+
for C H ONa (M + Na) requires 287.1406; found 287.1407.
1
9 20
5634 | Org. Biomol. Chem., 2012, 10, 5629–5635
This journal is © The Royal Society of Chemistry 2012

View Online
5
-Allylbiphenyl-2,4′-diol (30)
5 R. M. Denton, J. T. Scragg, A. M. Galofre, X. Gui and W. Lewis, Tetra-
hedron, 2010, 66, 8029.
6
R. M. Denton, J. T. Scragg and J. Saska, Tetrahedron Lett., 2011, 52,
554.
R. M. Denton and J. T. Scragg, Synlett, 2010, 633.
To a solution of 14 (10.0 mg, 37.3 μmol) in THF (1.00 mL) was
added t-BuOK (37.3 μL, 37.3 μmol of a 1.00 M solution in
THF) and the solution was heated to 50 °C for 1 h. The solution
was cooled to rt, diluted with EtOAc (10.0 mL), washed with
2
7
8
For syntheses of honokiol, see: (a) T. Takeya, T. Okubo and S. Tobinaga,
Chem. Pharm. Bull., 1986, 34, 2066–2070; (b) T. Esmui, G. Makado,
H. Zhai, Y. Shimizu, Y. Mitsumoto and Y. Fukuyama, Bioorg. Med.
Chem. Lett., 2004, 14, 2621–2625; (c) C.-M. Chen and Y.-Y. Liu, Tetra-
hedron Lett., 2009, 50, 1151; (d) S. Tripathi, M.-H. Chan and C. Chen,
Bioorg. Med. Chem. Lett., 2012, 22, 216; for a total synthesis of 4′-O-
methyl honokiol, see: (e) J.-H. Kwak, Y. A. Cho, J.-Y. Jang, S.-Y. Seo,
H. Lee, J. T. Hong, S.-B. Han, K. Lee, Y.-S. Kwak and J.-K. Jung, Tetra-
hedron, 2011, 67, 9401.
For recent work on the synthesis of analogues of honokiol and
related natural products, see: (a) L. Ma, J. Chen, X. Wang, X. Liang,
Y. Luo, W. Zhu, M. Peng, S. Li, S. Jie, A. Peng, Y. Wei and L. Chen,
J. Med. Chem., 2011, 54, 6469; (b) M. Cui and H. S. Kim, Synlett, 2012,
brine (3 × 10.0 mL), dried over MgSO and concentrated under
4
reduced pressure. Purification by flash chromatography (petrol–
EtOAc, 3 : 1) also gave 30 (3.70 mg, 37%) as a white solid, mp
1
04–106 °C, R 0.22 (petrol–EtOAc, 3 : 1).
f
1
H NMR: (400 MHz, CDCl ) δ 7.36 (d, J = 8.4 Hz, 2H), 7.07
3
(
dd, J = 8.0 and 2.0 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.95 (d,
J = 8.4 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 5.99 (ddt, J = 16.8,
0.0 and 6.8 Hz, 1H), 5.21 (br s, 1H), 5.10 (dd, J = 16.8 and 1.6
Hz, 1H), 5.07 (dd, J = 10.0 and 1.6 Hz, 1H), 3.36 (d, J = 6.8
9
1
311.
13
Hz, 2H); C NMR: (100 MHz, CDCl ) δ 155.3, 150.8, 137.8,
3
10 (a) X. Cheng, N. D. Harzdorf, T. W. Shaw and D. Siegel, Org. Lett.,
2010, 12, 1304; (b) N. A. McGrath, J. R. Binner, G. Markopoulos,
M. Brichacek and J. T. Njardarson, Chem. Commun., 2011, 47, 209;
(c) J. Wegner, S. V. Ley, A. Kirschning, A.-L. Hansen, J. M. Garcia and
I. R. Baxendale, Org. Lett., 2012, 14, 696.
11 For other biosynthetically inspired total syntheses of phenolic natural pro-
ducts, see: (a) S. A. Snyder, A. L. Zografos and Y. Lin, Angew. Chem.,
Int. Ed., 2007, 46, 8186; (b) S. A. Snyder and F. Kontes, J. Am. Chem.
Soc., 2009, 131, 1745; (c) S. A. Snyder, S. P. Breazzano, A. G. Ross,
Y. Lin and A. L. Zografos, J. Am. Chem. Soc., 2009, 131, 1753;
1
3
1
32.4, 130.5, 130.3, 129.5, 128.9, 127.7, 116.1, 115.7, 115.6,
9.4; IR: (CHCl ) 3594, 3556, 3082, 3060, 2979, 2905, 1639,
3
−1
611, 1516, 1493, 1331, 1260, 1171, 911, 839 cm . HRMS:
+
+
(ESI ) cald. for C H O Na (M + Na) requires 249.0891,
15 14 2
found 249.0907.
Notes and references
(d) S. A. Snyder, D. A. Wespe and J. M. von Hof, J. Am. Chem. Soc.,
2
2
011, 133, 8850; (e) S. A. Snyder, A. Gollner and M. I. Chiriac, Nature,
011, 474, 461; (f) S. A. Snyder, N. E. Wright, J. J. Pflueger and
1
For a reviews of biologically active lignans and neolignans isolated from
species, see: (a) Q. Song and N. H. Fischer, Rev. Soc. Quím. Méx., 1999,
S. P. Breazzano, Angew. Chem., Int. Ed., 2011, 50, 8629;
g) S. A. Snyder and Z. G. Brill, Org. Lett., 2011, 13, 5524.
6
, 211; (b) For a review, see: Y. Fukuyama, J.-M. Huang, Studies in
Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier, Amsterdam,
005, vol. 32, 395.
(
1
1
2 L.-K. Sy and G. D. Brown, J. Chem. Res., Synop., 1998, 476.
2
3 For a review on cascade reactions in total synthesis, see: K. C. Nicolaou,
D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134.
4 P. Magnus, N. Sane, B. P. Fauber and V. Lynch, J. Am. Chem. Soc., 2009,
2
M. Moriyama, J.-M. Huang, C.-S. Yang, H. Hioki, M. Kubo, K. Harada
and Y. Fukuyama, Tetrahedron, 2007, 63, 4243.
L.-K. Sy and G. D. Brown, Phytochemistry, 1996, 43, 1417.
Chavicol-(10), and the corresponding methyl ether, estragole (19), have
been isolated from numerous plant sources and are found in essential oils
of basil, fennel and anise. For the first report, see: J. F. Eykman, Ber.
Dtsch. Chem. Ges., 1890, 22, 2736; abstracted in J. Chem. Soc., 1890,
1
1
3
4
1
31, 16045.
5 A variable temperature NMR study has demonstrated that the oxy-
Michael reaction of a very similar hydroxybisenone is temperature depen-
dant; see: X. Wu, W. Liu, R. Nagarajan, J. Kumar, L. A. Samuelson and
A. L. Choll, Macromolecules, 2004, 37, 2322.
5
8, p. 135.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5629–5635 | 5635